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STUDY QUESTION Is the first-time redeemed prescription of antidepressants predicted by the level of infertility-related stress in women seeking ART treatment? SUMMARY ANSWER Infertility-related stress in the personal and marital domains and general physical stress reactions were significant predictors of a first redeemed prescription of antidepressants after ART treatment in this 10-year follow-up cohort study. WHAT IS KNOWN ALREADY The literature has found inconsistent findings regarding the association between infertility-related stress and later psychological adjustment in fertility patients. The association between infertility-related stress and later prescription of antidepressants had never been explored in long-term cohort studies. STUDY DESIGN, SIZE, DURATION All women (n = 1169) who participated in the Copenhagen Cohort Multi-centre Psychosocial Infertility (COMPI) cohort study in the year 2000 (questionnaire data) were linked with the register-based Danish National ART-Couple (DANAC) I cohort, which includes women and their partners having received ART treatment from 1 January 1994 to 30 September 2009. The study population were among other national health and sociodemographic registers further linked with the Danish National Prescription Registry. PARTICIPANTS/MATERIALS, SETTING, METHODS Women initiating ART treatment were followed until they had redeemed the first prescription of antidepressants or until 31 December 2009. Logistic regression analyses were conducted to test the association between general physical stress reactions and infertility-related stress in the personal, marital and social domains, respectively, and a future redeemed prescription of antidepressants. Age, education level, marital status, number of fertility treatments prior to study inclusion and female infertility diagnosis were included as covariates in the adjusted analyses. Further, the analysis was stratified according to childbirth or no childbirth during follow-up. MAIN RESULTS AND THE ROLE OF CHANCE The final sample consisted of 1009 women with a mean age of 31.8 years. At study inclusion, women had tried to conceive for an average of 3.45 years. At 10-year follow-up, a total of 13.7% of women had a first redeemed prescription of antidepressant medication. The adjusted odds ratio (OR) showed that high general physical stress predicted the later prescription of antidepressants (adjusted (adj) OR = 2.85, 95% confidence interval (CI) 1.96-4.16). Regarding infertility-related stress domains, high personal stress (adj OR = 2.14, 95% CI 1.46-3.13) and high marital stress (adj OR = 1.80, 95% CI 1.23-2.64) were significantly associated with the later prescription of antidepressants. Social stress was not significantly associated with the future redeemed prescription of antidepressants (adj OR = 1.10, 95% CI 0.76-1.61). Among women not having achieved childbirth during follow-up, the risk of a first-time prescription of antidepressants associated with infertility-specific stress was higher compared to the risk among women having childbirth during follow-up. LIMITATIONS, REASONS FOR CAUTION This study did not account for potential mediating factors, such as negative life events, which could be associated with the prescription of antidepressants. Second, we are not able to know if these women had sought psychological support during follow-up. Additionally, antidepressants might be prescribed for other health conditions than depressive disorders. WIDER IMPLICATIONS OF THE FINDINGS Our results suggest that women presenting high infertility-related stress in the personal and marital domains were at higher risk of redeemed first-time prescription of antidepressants after ART, independently of having delivered a child or not after initiation of ART treatment. Women would benefit from an initial screening specifically for high infertility-related stress. The COMPI Fertility Problem Stress Scales can be used by clinical staff in order to identify women in need of psychological support before starting ART treatments. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Portuguese Foundation for Science and Technology (FCT) under an individual doctoral grant attributed to the first author (SFRH/BD/103234/2014). The establishment of the DANAC I cohort was funded by Rosa Ebba Hansen's Fund. The COMPI Infertility Cohort project was supported by The Danish Health Insurance Fund (J.nr. 11/097-97), the Else and Mogens Wedell-Wedellsborgs Fund, the manager E. Danielsens and Wife's Fund, the merchant L.F. Foghts Fund, the Jacob Madsen and Wife Olga Madsens Fund. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER NA.