HIV-positive lactating women may be at high risk of weight loss due to increased caloric requirements and postpartum physiological weight loss. Ten percent weight loss is associated with a higher risk of mortality in HIV-positive patients and this alone is a criterion for highly active antiretroviral therapy (HAART) initiation where CD4 counts are not available. However, no study has investigated this association in lactating postpartum women. We investigated whether 10% weight loss predicts death in postpartum HIV-positive women. A total of 9207 HIV-negative and 4495 HIV-positive mothers were recruited at delivery. Women were weighed at 6 weeks, 3 months, and every 3 months thereafter for up to 24 months postpartum and data on mortality up to 2 years were collected. The median duration of breastfeeding was longer than 18 months. Among HIV-positive women, the independent predictors of ≥10% weight loss were CD4 cell count, body mass index, and household income. Mortality was up to 7.12 (95% CI 3.47-14.61) times higher in HIV-positive women with ≥10% weight loss than those without weight loss. Ten percent weight loss in postpartum lactating HIV-positive women was significantly predictive of death. Our findings suggest that 10% weight loss is an appropriate criterion for HAART initiation among postpartum breastfeeding women.