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OBJECTIVES This study characterizes the molecular mechanisms of trimethoprim resistance and antibiotics resistance of Streptococcus pneumoniae isolates from HIV-infected adults in Dar es Salaam, Tanzania. METHODS A total of 1877 nasopharyngeal swabs were collected and screened for pneumococcal colonization from 537 newly diagnosed individuals with HIV at four clinic visits during a one-year follow-up from 2017 -2018 as part of the randomized clinical trial CoTrimResist (ClinicalTrials.gov identifier: NCT03087890). RESULTS A total of 76 pneumococcal isolates were obtained. Sixty percent (42/70) of isolates that could be serotyped were conjugate vaccine serotypes, pneumococcal conjugate vaccine 23 (PCV23). The majority (73.7%, 56/76) was penicillin non-susceptible minimum inhibitory concentration (MIC) 0.06 - 2 μg//ml. Isolates were frequently resistant to cotrimoxazole (71.1%) but less so to azithromycin (22.4%), erythromycin (21.1%), chloramphenicol (18.4%), tetracycline (14.5%), clindamycin (10.5%) and levofloxacin (none). Twenty-six percent were multi-drug resistant (resistant to ≥3 antibiotic classes). Vaccine-type pneumococci were resistant to more classes of antibiotics; more frequently resistant to erythromycin, azithromycin, clindamycin and tetracycline, and had higher MIC-values towards penicillin (Median 0.19; range 0.002-1.5) versus non-vaccine types (Median 0.125; range 0.012-0.25), p = 0.003. Cotrimoxazole-resistant isolates carried from 1 to 11 different mutations in dihydrofolate reductase gene, the most common being Ile100Leu (100%), Glu20Asp (92%), Glu94Asp (61%), Leu135Phe (57%), His26Tyr (53%), Asp92Ala (53%) and His120Gln (53%). CONCLUSIONS In conclusionStreptococcus pneumoniae isolated from HIV-diagnosed patients were frequently non-susceptible to penicillin and cotrimoxazole. Most isolates carried multiple mutations in the dihydrofolate reductase gene.