The aim of this study was to identify factors associated with serum triglyceride (TG) evolution in HIV-1-infected patients when highly active antiretroviral treatment (HAART) with or without protease inhibitors (PI) was introduced. Among 3191 patients of the Aquitaine Cohort (multirisk, both genders, multiple treatment patterns) observed during 1996 through 1998, 1429 had at least two measurements of TG, viral load, and CD4 cell count. Median follow-up was 21 months (interquartile range [IQR], 11-26) and median number of TG measures was 6 (IQR, 3-10). Median TG at baseline was 1.32 mmol/L (IQR, 0.91-2.05) and increased significantly over time (+2.5% for 100 days; 95% confidence interval [CI], 1.9-3.1). Longitudinal analysis of variations of TG was performed using mixed models. In crude analysis, baseline TG was higher in men, in those aged over 36 years, and in homosexuals. The following time-dependent variables were associated with an increase of TG: body weight increasing to >65 kg, diagnosis of AIDS, CD4 cell count falling to <50 cells/mm3, viral load falling to <500 cp/ml, and introduction of nucleoside analogues and PIs. In multivariate analysis, age >36 years (change of +17% of the TG level; 95% CI, 11-24), homosexuals (+13%; 95% CI, 4-23), AIDS stage (+12%; 95% CI, 5-19), weight >65 kg (+7%; 95% CI, 2-12) and PI (+21%; 95% CI, 17-27) remained significant. Factors identified before the availability of PI remain important but HAART with PI is a new major contributing factor to increased TG levels.