Low high-density lipoprotein-cholesterol (HDL-C) levels have been associated with cardiovascular risk in non-HIV populations. Limited information exists on the prevalence of low HDL-C in HIV- infected patients and related factors remain largely unknown. The aims of this study were to estimate the prevalence and characteristics of low HDL-C levels in HIV-infected patients. A cross-sectional study was performed in consecutive HIV-infected patients cared for in an outpatient HIV clinic on the Mediterranean coast of Spain during a 2-month period (September 15, 2003 to November 15, 2003). HDL-C levels below 40 mg/dL were considered low. We analyzed data from 219 patients, 167 of whom were on antiretroviral therapy. The majority (45.20 %) were on non-nucleoside reverse transcriptase inhibitors (NNRTI); 22.83 % were on treatment with protease inhibitors. The prevalence of low HDL-C levels was 44.74 % (98 of 219 patients). In multivariate analysis, hypertriglyceridemia (triglycerides >150 mg/dL; odds ratio [OR], 5.65; 95% confidence interval [CI], 2.85-11.23; p = 0.0001), HIV-1 RNA viral load greater than 50 copies per milliliter (OR, 3.15; 95% CI, 1.63-6.109; p = 0.001) and antiretroviral therapy with regimens other than NNRTIs-based regimens (OR, 2.17; 95% CI, 1.12-4.16; p = 0.021) were associated with low HDL-C levels. These data indicate that prevalence of low HDL-C among HIV-infected patients from this cohort was very high. Low HDL-C was related to triglyceride levels, HIV-1 RNA viral load and antiretroviral therapy composition. Undetectable viral load and treatment with NNRTIs are protective factors, whereas hypertriglyceridemia is directly associated with low HDL-C levels.