Background: Morphological abnormalities (lipoatrophy and central fat accumulation) and metabolic changes (dyslipidaemia and glucose regulation impairment) have emerged as components of lipodystrophy and as major tolerability issues with long-term use of highly active antiretroviral therapy (HAART) in HIV-positive patients. Protease inhibitors (PIs) are recognized as having the greatest impact in terms of metabolic complications, followed by nucleoside reverse transcriptase inhibitors, while the non-nucleoside reverse transcriptase inhibitors (NNRTIs) have the least impact. In particular, regimens based on the NNRTI nevirapine have been shown to achieve significant metabolic benefits and may help to improve dyslipidaemia. Improvements in body shape changes associated with lipodystrophy have also been reported when nevirapine replaced a PI in long-term triple therapy. Objective: The objective of this cross-sectional observational ('real-world') study was to investigate the effect of three HAART regimens plus stable nevirapine therapy on morphological and metabolic components of lipodystrophy in HIV-infected patients. Methods: Consecutive patients (aged 18 years) with serologically documented HIV infection, who had received HAART for at least 2 years and who had been diagnosed with lipodystrophy, were followed up as outpatients at the metabolic clinic of the University of Modena and Reggio Emilia, Modena, Italy. Patients received stable nevirapine therapy plus fixed-dose combinations of tenofovir disoproxil fumarate plus emtricitabine (Truvada[R]; TVD), zidovudine plus lamivudine (3TC) [Combivir[R]; CBV], or abacavir plus lamivudine (Kivexa[R]; KVX). Multivariate regression analyses were performed to analyse predictors of four components of lipodystrophy: lipoatrophy using leg fat mass measured by dual-emission x-ray absorptiometry (DXA), fat accumulation using waist circumference, dyslipidaemia using apolipoprotein (Apo)B/ApoA1 ratio, and glucose intolerance using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Results: Overall, 101 patients were enrolled (TVD group = 61, CBV group = 20, KVX group = 20); 191 observations were analysed. Male sex was associated with reduced leg fat mass, while age and body mass index (BMI) were associated with increased leg fat mass (all p Conclusion: HAART including nevirapine has a limited impact on components of lipodystrophy in patients with HIV infection. Further studies are needed to verify if nevirapine overcomes the expected distinct lipodystrophy risk profile associated with different nucleoside backbone therapies.