Stavudine is no longer recommended for use in first-line antiretroviral therapy (ART), but it remains in high demand worldwide because it is affordable. We report the clinical presentation and incidence of severe hyperlactatemia (SL) in HIV-infected adults who initiated ART between April 2005 and May 2009 in Côte d'Ivoire, West Africa. In a prospective cohort study at the HIV care center affiliated with the National Centre for Blood Transfusion, we used standardized forms to record baseline and follow-up data. We measured serum lactate levels for all adults on ART who showed signs of hyperlactatemia. SL was defined as serum lactate >2.5 mmol/liter. Overall, 806 adults initiated ART. Among the 591 patients (73%) on stavudine-containing regimens, 394 were women (67%); the median pre-ART CD4 count was 150/mm3 and the median body mass index was 20.9 kg/m2. These patients were followed for a median of 28 months. We detected SL only among patients taking stavudine. The incidence of SL was 0.55/100 person-years (PY) (95% CI 0.47-0.63) overall and 0.85/100 PY among women (95% CI 0.75-0.95). Among the eight patients with SL, 100% lost >9% of body weight before diagnosis, 100% had serum lactate >4 mmol/liter (range 4.2-12.1), 50% had pre-ART BMI >25 kg/m2, and three patients died (38%), accounting for 6.4% of deaths among patients taking stavudine. As long as HIV clinicians continue to use stavudine in sub-Saharan Africa, they should watch out for acute unexplained weight loss in patients taking ART, particularly among women and patients with high pre-ART BMI.