Strains of the Mycobacterium avium complex (MAC) yield opaque and transparent colonial variants when cultivated in vitro. The transparent variants are more virulent than the opaque for animals, but little is known about the respective roles of these colonial variants in humans. To assess which variant infects humans, various blood fractions from eight patients with MAC bacteremia were plated directly onto 7H10 agar. In cell fractionation studies, all the M. avium complex CFU were associated with leukocytes and none were found free in plasma. All colonies on the primary culture plate exhibited the transparent phenotype. However, during subculture in 7H9 broth or on Lowenstein-Jensen agar, opaque variants appeared in seven of eight strains. Isogenic pairs of transparent and opaque variants were prepared and used to infect in vitro human monocyte-derived macrophages from healthy seronegative individuals. Transparent variants invariably grew inside macrophages, but only one of seven opaque variants did so. These observations indicate that the bacteremia of M. avium complex in acquired immunodeficiency syndrome patients consists exclusively of the transparent variants, perhaps because these variants are able to multiply inside macrophages. In contrast, opaque variants appear after in vitro subculture and are controlled by human macrophages, consistent with their reduced virulence in animals.