OBJECTIVE: To assess the efficacy and safety of two different dosages of cotrimoxazole (CTX) in prophylaxis in HIV-positive new smear-positive pulmonary tuberculosis (TB) patients in Blantyre, Malawi. METHOD: Randomized, double-blind trial using 480 and 960 mg of CTX given to new TB patients, who were followed up until the end of the tuberculosis treatment. The primary outcome was survival. The outcome in the two groups was also compared with an unselected cohort of similar patients registered in Zomba, Malawi in 1995 and new smear-positive patients registered in the National Tuberculosis Programme in 1999. The secondary outcome was the occurrence of (opportunistic) events, especially bacterial pneumonia. RESULTS: There were no statistically significant differences in mortality and bacterial pneumonia between the groups receiving the two different dosages. The case fatality rate at the end of the tuberculosis treatment was 15.4% in the 480 mg group and 14.0% in the 960 mg group. This was lower than the case fatality rate in the Zomba cohort (19.2%, P = 0.10) and lower than the case fatality rate in the national programme (21.0%, P < 0.001). CTX was well tolerated. Compliance was fair. CONCLUSIONS: CTX prophylaxis may have a beneficial effect on mortality and morbidity in HIV-infected smear-positive tuberculosis patients in Malawi. The efficacy of both dosages is not significantly different. The intervention is cheap and easy to implement. These results would support implementation of CTX in this patient group until better strategies are available or evidence is convincingly presented to suggest that its benefit is marginal.