BACKGROUND: Lactic acidosis is a rare but life-threatening complication of combination antiretroviral therapy (CART). Asymptomatic or mildly symptomatic episodes of hyperlactatemia are more frequent, but their clinical relevance is unknown. METHODS: The incidences of, risk factors for, and courses of hyperlactatemia and lactic acidosis were prospectively assessed in the following 3 groups at the Zurich center of the Swiss HIV Cohort Study: persons already receiving CART at baseline, treatment-naive persons who initiated CART during the observation period, and persons who received no CART before or during the observation period. RESULTS: During 4788 person-years of follow-up, a total of 22,678 lactate assessments were performed for 1566 persons; 662 (42.3%) had at least 1 lactate level measurement of > 2.4 mmol/L, and 49 (3.1%) had severe hyperlactatemia (lactate level of > 5.0 mmol/L). The incidence of hyperlactatemia was 227 cases (95% confidence interval [CI], 210-245) and 59 cases (95% CI, 38-93) per 1000 person-years of follow-up among persons with and persons without CART, respectively. During the observation period, the incidence decreased from 459 cases (95% CI, 415-508) to 85 cases (95% CI, 76-107) per 1000 person-years of follow-up, respectively, because of changing CART prescription patterns. Severe hyperlactatemia occurred in treated persons only. In multivariable Cox proportional hazards models, significant risk factors for severe hyperlactatemia were regimens containing stavudine and didanosine (hazard ratio [HR], 6.65; 95% CI, 2.70-16.3) and regimens containing efavirenz (HR, 2.85; 95% CI, 1.31-6.21). Lactic acidosis was diagnosed in 4 of 1566 persons, all of whom were receiving stavudine and didanosine. CONCLUSIONS: Hyperlactatemia was frequently observed in all 3 groups, but severe hyperlactatemia and lactic acidosis were rarely observed among persons who received CART. Lactate monitoring appears to be indicated primarily for persons receiving stavudine and didanosine and for persons who are symptomatic. Long-term follow-up is needed to investigate the risk of novel treatment regimens for hyperlactatemia.