Background: HAART has dramatically changed the prognosis of AIDS, but has led to long-term toxicities of antiretroviral drugs. A major chronic complication is the metabolic syndrome (MS), including hyperlipidemia, lipodystrophy (LD), and impaired glucose metabolism. Methods: A cross-sectional study of a series of 582 patients from the Serbian HIV/AIDS cohort, treated with HAART for a mean period of 3.3 +/- 2.1 years (range 1-10), was performed to evaluate the prevalence and risk factors for MS during HAART. Results: The prevalence of LID was 29.1%, with a 100% probability of development after 10 years of treatment. Risk factors for LD included female gender(OR 1.7, 95% CI 1.0-2.7, P = 0.02), age > 40 (OR 1.7,95% CI 1.1-2.7, P = 0.01) and AIDS at HAART initiation (OR 1.9,95% CI 1.2-2.2, P < 0.01), as well as prolonged usage of NRTIs (OR 2.7, 95% CI 1.6-4.5, P < 0.01). The NNRTI-based regimens were less likely to induce LD than those PI-based (OR 1.87, 95% CI 1.2-2.9 vs. OR 3.7, 95% CI 2.3-6.1, respectively). Hyperlipidemia occurred in 47% of the patients, and was associated with male gender (OR 2.2, 95% CI 1.4-3.5, P < 0.01) and prolonged usage of PI + NNRTI HAART (OR 3.0, 95% CI 1.8-4.9, P < 0.01). In contrast, regimens composed of 2 NRTI + NNRTI were less likely to induce hyperlipidemia (OR 0.4, 95% CI 0.3-0.7, P = 0.03). Glucose intolerance and/or diabetes mellitus was recorded in 9.6%, if with AIDS at HAART initiation (OR 3.7, 95% CI 1.2-11.4, P < 0.01), male gender (OR 5.2, 95% CI 1.8-15.1, P < 0.01) and age > 40 (OR 2.6, 95% CI 1.1-6.3, P = 0.02). Conclusion: MS seems an inevitable consequence of long-term successful HAART. (C) 2008 Elsevier Masson SAS. All rights reserved.