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We assessed the incidence and determinants of bacteremia, pneumonia, and sinusitis/otitis in HIV-positive people receiving cotrimoxazole (CTX) or dapsonepyrimethamine (DP) for primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis (TE) within a randomized clinical trial. In total, 244 patients were randomized: 122 were assigned to CTX and 122 to DP. In the cohort, 22 bacteremia, 63 pneumonia, and 39 sinusitis/otitis cases were observed. Incidence rates of bacteremia, pneumonia, and sinusitis/otitis as well as the 2-year probability of remaining free from any bacterial infection were not significantly different between the two groups. At multivariate analysis, the risks of developing bacteremia and pneumonia were found to be independently increased by the use of a central venous catheter (hazard ratio [HR], 4.48; p < .05 and HR, 4.13; p < .01, respectively) and by hospitalization (HR, 28.82; p < .05 and HR, 10.15; p < .05, respectively). In conclusion, CTX at the dosage employed for primary PCP/TE prophylaxis does not seem to protect against bacterial infections more than second-line DP.