OBJECTIVE Anemia is an important negative predictor for survival with disseminated Mycobacterium avium complex (MAC) infection in the acquired immunodeficiency syndrome (AIDS). We analyzed the differences in AIDS patients with and without MAC infection with regard to anemia, severity of human immunodeficiency virus (HIV) infection, bone marrow morphology, and bone marrow erythroid progenitor colony growth (BFU-E and CFU-E). In addition, we determined the in vitro effect of sera obtained from these patients on normal BFU-E and CFU-E. A possible role of macrophages in the suppression of erythropoiesis was examined by studying in vitro the effect of supernatants from MAC-infected macrophages on cultured BFU-E and CFU-E. METHODS Hematocrit, serum levels of p24 antigen, erythropoietin, and CD4-positive cell count were determined in 14 AIDS patients with and 24 without MAC infection. Bone marrow erythropoietic and granulocytic progenitor cells from 15 normal individuals, from 12 AIDS patients with MAC infection, and from 10 AIDS patients without MAC infection were cultured on methylcellulose. In addition, progenitor cells from normal individuals were cultured in the presence, and in the absence, of sera obtained from AIDS patients with (14), or without (24), MAC infection. Last, we studied the effect of supernatants (SNs) from MAC and Mycobacterium tuberculosis-infected macrophages on erythropoietic progenitor cell growth. RESULTS The anemia in AIDS patients with MAC infection was associated with a selective suppression of erythropoietic progenitors despite bone marrow morphology that was indistinguishable from that in patients without MAC infection. The degree of anemia could not be explained on the basis of severity of HIV infection or a deficiency of erythropoietin production. Bone marrow mononuclear cells from AIDS patients with MAC generated significantly fewer erythroid progenitor colonies (BFU-E and CFU-E) than equivalent cells from AIDS patients without MAC infection (p < 0.05). Sera from MAC-infected AIDS patients were markedly inhibitory to the erythroid progenitors as compared with sera from patients without MAC infection (p < 0.001). SNs from MAC-infected macrophages were markedly inhibitory to the erythroid progenitors (BFU-E and CFU-E) as compared with the myeloid progenitors (CFU-GM). CONCLUSIONS The profound anemia in MAC-infected AIDS patients is due to suppression of erythroid progenitors by a soluble factor(s) in the serum. The data suggest that the soluble factor(s) is probably elaborated by macrophages.