Man and rhesus monkey may develop anemia during treatment with the broad-spectrum antiviral ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide). To assess whether the anemia is due to decreased production of erythrocytes, increased destruction, or a combination of both factors, the transport of ribavirin into erythrocytes and the drug's effect on the osmotic fragility, deformability, and half-life of erythrocytes were evaluated. The rate of uptake of ribavirin by erythrocytes was species and concentration dependent. Monkey cells accumulated the largest concentration of drug followed by human and rat cells. Monkey and human red cells, pretreated in vitro with ribavirin, retained 77 and 45% of the drug, respectively, when reincubated for 2 hr in drug-free medium. Rat red cells retained only 20% of their initial ribavirin content. Neither osmotic fragility nor deformability was altered by exposure of red cells to ribavirin in vitro. The half-life of 1,3-[3H]diisopropyl fluorophosphate (DFP)-labeled erythrocytes was measured in rhesus monkeys treated intramuscularly (im) for 10 days with either 15 or 60 mg/kg of ribavirin. A dose-related decrease in red cell survival was observed from Day 0 to 28. Thereafter, red cell half-lives were comparable to control values. These data indicate that ribavirin at a dose as low as 15 mg/kg decreases the half-life of red cells. This effect was reversible upon discontinuation of the drug. At 60 mg/kg, ribavirin also inhibited the release of red cells from the bone marrow. Termination of treatment was followed by release of red cells from the bone marrow as indicated by a drop in the specific activity of [3H]DFP-labeled red cells and marked reticulocytosis. No inhibition of red cell release from the bone marrow was seen in the low-dose group. These data suggest that ribavirin can decrease red cell survival as well as inhibit red cell release from the bone marrow. Both effects appear fully reversible when treatment is withdrawn.