Human immunodeficiency virus (HIV) infection has frequently been associated with vitamin D deficiency as well as chronic inflammatory response. We tested the hypothesis of an independent relationship between serum concentrations of 25-hydroxyvitamin D [25(OH)D] and high-sensitivity C-reactive protein (CRP) in a cohort of HIV-positive people. A cross-sectional survey was conducted among 316 HIV-positive people (181 men and 135 women) aged 16 to 60 years residing in the Kathmandu Valley, Nepal. Serum high-sensitivity CRP concentrations and serum 25(OH)D levels were measured by the latex agglutination nephelometry method and the competitive protein-binding assay, respectively. The relationship between serum CRP concentrations and 25(OH)D serum level was assessed using multiple logistic regression analysis with adjustment of potential cardiovascular and HIV-related factors. The proportions of participants with 25(OH)D serum levels < 20 ng/ml, 20–30 ng/ml, and ‡ 30 ng/ml were 83.2%, 15.5%, and 1.3%, respectively. The mean 25(OH)D serum levels in men and women were 15.3 ng/ml and 14.4 ng/ml, respectively. Participants with a 25(OH)D serum level of < 20 ng/ml had a 3.2-fold higher odds of high CRP ( > 3mg/liter) compared to those with a 25(OH)D serum level of ‡ 20 ng/ml ( p = 0.005). Men and women with a 25(OH)D serum level of < 20 ng/ml had 3.2- and 2.7-fold higher odds of high CRP ( > 3mg/liter), respectively, compared to those with a 25(OH)D serum level of ‡ 20 ng/ml. The relationships remained significant only in men ( p = 0.02) but not in women ( p = 0.28). The risk of having a high level of inflammation (CRP > 3mg/liter) may be high among HIV-positive men and women with a 25(OH)D serum level of < 20 ng/ml