Controversies over the vitamin D receptor (VDR) acting as a susceptibility factor in Mycobacterium sp. infections may be the result of incorrect population stratification. The risk of leprosy occurrence conditioned by VDR polymorphism was investigated by stratifying the population of a highly endemic Brazilian region into negative and positive Mitsuda responses. Leprosy patients (102) and a group of healthy nonconsanguineous household contacts (68) were genotyped for the VDR TaqI polymorphism (T/t). TT and Tt genotypes were not considered to be risk factors as their odds ratios (OR) were not different from those presented by the negative Mitsuda response individuals. The combination of the tt genotype and the negative Mitsuda test provided an occurrence rate 13 times higher in leprosy patients than in controls with positive Mitsuda responses. This suggests that there is a higher risk of leprosy development when individuals carry this unfavorable combination, and demonstrates a possible synergistic role of these two variables in leprosy susceptibility via effects on cellular immunity.