Vitamin D receptor (VDR) gene variants are shown to regulate immune response in tuberculosis. We studied the influence of VDR promoter (Cdx-2 and A1012G), 3' untranslated region (Apa I, Bsm I, and Taq I) and start codon (Fok I) polymorphisms on 1,25(OH)(2)D(3)-modulated IL-12p40, IFN-gamma, IL-10, and IL-5 response to live Mycobacterium tuberculosis and its culture filtrate antigen (CFA) in 60 normal healthy subjects and 51 pulmonary tuberculosis patients. In peripheral blood mononuclear cell cultures with CFA and 1,25(OH)(2)D(3), IL-12p40, and IFN-gamma levels were significantly decreased (p < 0.05) and IL-10 levels were significantly increased (p < 0.05) in patients with GG genotype. The extended genotype bbaaTT (baT haplotype) was associated with decreased IL-12p40 and IFN-gamma levels and significantly increased IL-10 levels (p < 0.05). The Cdx-2 GG genotype and baT haplotype are associated with a suppressed Th1 and increased IL-10 response, which suggests that 1,25(OH)(2)D(3) probably through the VDR polymorphic variants augments the anti-inflammatory response at the site of M. tuberculosis infection.