Dendritic-cell-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing non-integrin (DC-SIGN), a pattern recognition receptor, is associated with immune functions and is also exploited by HIV-1 and Mycobacterium tuberculosis as a part of their immune evasion strategy. In the present study we investigated whether variants in the DC-SIGN encoding CD209 gene are associated with susceptibility to or protection against HIV-1 infection as well as development of tuberculosis (TB) among HIV-1 infected south Indian patients. CD209 gene variants in the promoter region (-336 and -139), in the intron and 3'-untranslated regions (In2+11 and 2281) were studied using polymerase chain reaction-based genotyping methods in 131 HIV patients without TB (HIV+TB-) and 107 HIV patients with TB (HIV+TB+), 107 HIV negative pulmonary TB patients (HIV-PTB+) and 157 healthy controls. Results revealed a decreased frequency of -336 G/G genotype among all HIV patients compared to healthy controls and -336 G/G genotype was not observed among HIV+TB- individuals (p=0.005; odds ratio (OR) 0 (95% confidence intervals (CI) 0-0.46); Peto's odds ratio 0.149 (95% CI 0.045-0.50)). Among HIV+ patients, those with TB had a significantly increased frequency of -336 G/G genotype (p=0.003; OR undefined; Peto's odds ratio 9.8 (95% CI 2.2-44.3)) compared to those without TB. Other polymorphisms were not significantly different between the various study groups. The results suggest that -336 G/G genotype while associated with protection against HIV-1 infection the same genotype is also associated with susceptibility to HIV-TB among south Indians.