Background Although it significantly improves HIV-related outcomes, some components of combination antiretroviral therapy (ART) cause lipodystrophy syndrome. The composition of combination ART has changed over time but the impact on lipodystrophy prevalence is unknown. Methods: One hundred HIV-infected males underwent dual-energy X-ray absorptiometry scanning, serum lipid testing and completed a questionnaire in a cross-sectional study in 2010. Thirty-four participants of a 1998 study cohort were re-evaluated in 2010. The same parameters were used to define and compare lipodystrophy, metabolic syndrome and cardiovascular disease (CVD) risk in the two time periods. Results: In 2010, the prevalence of lipodystrophy was lower when compared with 1998 (53% v. 69%, P = 0.012), despite higher mean age (51.8 v. 42.1 years, P < 0.0001), duration of HIV (165 v. 86 months, P < 0.0001), ART exposure (129 v. 38 months, P < 0.0001), CD4+ cell count (601 v. 374 cells µL−1, P < 0.0001) and waist circumference (95.5 v. 89.9 cm P < 0.0001). Cholesterol (5.0 v. 5.6 mmol L−1, P = 0.0001) and triglycerides (1.9 v. 3.7 mmol L−1, P < 0.0001) were significantly lower in 2010. Factors associated with an increased risk of lipodystrophy in 2010 were duration of HIV infection and low-density lipoprotein cholesterol, whereas current tenofovir or abacavir use was associated with a decreased risk of lipodystrophy. On multivariate analysis low-density lipoprotein cholesterol (OR, 2.65; CI, 1.4–4.9) remained significant for an increased risk and current tenofovir or abacavir use with reduced risk of lipodystrophy (OR, 0.096; CI, 0.011–0.83). In 2010 there was a higher prevalence of metabolic syndrome (33 v. 28%) and higher median Framingham CVD risk (9.9% (5.7–14.6) v. 8.2% (4.5–12.9). Conclusion: Despite ageing and longer duration of HIV infection and ART exposure, the prevalence of lipodystrophy in HIV-infected men significantly declined over a 12-year period. However, a trend exists toward a higher prevalence of metabolic syndrome and increased CVD risk.