Subjects with neutrophil myeloperoxidase (MPO) deficiency have been rarely reported. In part this may be due to the lack of a simple screening technique that would detect them. With the routine use of a cytochemical leukocyte differential counter that employs MPO stains, over a 40-mo a period 8 unrelated probands with partial MPO-deficiency and one with complete deficiency were identified. Family studies have identified 23 additional, partially deficient subjects. The largest pedigrees demonstrate that the carrier state or partial MPO deficiency is inherited in an autosomal dominant pattern. Leukocytes from a subject with complete MPO deficiency and from some subjects with partial deficiency have impaired bactericidal activity against S. aureus. Superoxide generation was increased and chemiluminescence decreased in MPO-deficient leukocytes. Eleven subjects were prospectively followed for 18–30 mo. Only two partially deficient subjects have had serious infections consisting of recurrent streptococcal cellulitis and aseptic meningitis. These data suggest that leukocyte MPO deficiency is a common inherited defect that results in minimal clinical problems, supporting the concept of multiple leukocyte bacterial killing systems.