Evidence from genetic association and twin studies indicates that susceptibility to tuberculosis (TB) is under genetic control. One gene implicated in susceptibility to TB is that encoding interleukin-10 (IL10). In a group of 2010 Ghanaian patients with pulmonary TB and 2346 healthy controls exposed to Mycobacterium tuberculosis, among them 129 individuals lacking a tuberculin skin test (PPD) response, we genotyped four IL10 promoter variants at positions -2849 , -1082 , -819 , and -592 and reconstructed the haplotypes. The IL10 low-producer haplotype -2849A/-1082A/-819C/-592C, compared to the high-producer haplotype -2849G/-1082G/-819C/-592C, occurred less frequent among PPD-negative controls than among cases (OR 2.15, CI 1.3-3.6) and PPD-positive controls (OR 2.09, CI 1.2-3.5). Lower IL-10 plasma levels in homozygous -2849A/-1082A/-819C/-592C carriers, compared to homozygous -2849G/-1082G/-819C/-592C carriers, were confirmed by a IL-10 ELISA (p = 0.016). Although we did not observe differences between the TB patients and all controls, our results provide evidence that a group of individuals exposed to M. tuberculosis transmission is genetically distinct from healthy PPD positives and TB cases. In these PPD-negative individuals, higher IL-10 production appears to reflect IL-10-dependent suppression of adaptive immune responses and sustained long-term specific anergy.