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RATIONALE The six-minute walk distance is an important clinical and research metric in pulmonary arterial hypertension; however, there is no consensus about what minimal change in six-minute walk distance is clinically significant. OBJECTIVES We aimed to determine the minimal clinically important difference in the six-minute walk distance. METHODS We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for pulmonary arterial hypertension that were submitted to the United States Food and Drug Administration to derive minimal clinically important differences in the six-minute walk distance. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in six-minute walk distance to the change in the Medical Outcomes Survey Short Form Physical Component Score. MEASUREMENTS AND MAIN RESULTS The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with pulmonary arterial hypertension respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 m (95% CI: 27, 38) which was almost identical to that in the validation sample (36 m [95% CI: 29, 43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. CONCLUSION We estimated a six-minute walk distance minimal clinically important difference of ~ 33 m for adults with pulmonary arterial hypertension. Our findings can be applied to the design of clinical trials of therapies for pulmonary hypertension.