Human mannan‐binding protein (MBP) is a serum lectin that participates in the immune defence by mediating phagocytosis and activation of complement. Variant MBP alleles causing dominant low‐serum concentrations have high frequencies in all populations studied, and therefore, low MBP concentrations may confer selective advantages to those individuals carrying the variant alleles. Mycobacterium leprae, the causative agent of leprosy, is an obligate intracellular parasite dependent on phagocytosis to invade host cells. The serum concentrations of MBP in 36 Ethiopian patients (median: 1688μgl^‐1) with lepromatous or borderline lepromatous leprosy were significantly (P<0.001) higher than in 26 healthy Ethiopian blood donors (median: 368μgl^‐1) Only 17% of the patients vs. 58% of the donors (P = 0.0019) had the relatively low MBP concentrations usually associated with variant alleles. Functional studies revealed that M. leprae and M. tuberculosis sonicates bind MBP as strongly as pure mannan. These observations suggest a role for mycobacteria as a selective force in the positive selection of alleles causing low levels of MBP and warrant genetic studies of patients infected with these bacteria.