OBJECTIVE To describe a retrospective study of six HIV-positive individuals with compensated metabolic acidosis while receiving intravenous trimethoprim/sulfamethoxazole (TMP/SMX). METHODS Six HIV-infected patients were treated for Pneumocystis carinii pneumonia (PCP) with high-dose intravenous TMP/SMX. In spite of a favorable clinical and radiologic course, all six patients developed compensated metabolic acidosis 3-5 days after the start of treatment. This potential complication of TMP/SMX use was successfully managed with conservative treatment (cessation of therapy with or without additional administration of intravenous bicarbonate). CONCLUSIONS TMP/SMX is first-line therapy for PCP in HIV-positive individuals, despite a high frequency of toxic effects in these patients. In addition to the cases reported here, only two other reports of metabolic acidosis secondary to TMP/SMX use in HIV-infected patients have been published in the literature. The precise mechanism of this untoward effect is not fully understood, although renal tubular acidosis induced by TMP/SMX could be implicated. CONCLUSIONS TMP/SMX toxicity should be considered in the differential diagnosis of HIV-infected patients with acute metabolic acidosis. Metabolic acidosis can be expected to resolve shortly after discontinuation of the drug.