An estimated 2.7 million people in the United States are infected with the hepatitis C virus (HCV), yet the influence of HCV infection on the peripheral blood count remains unknown. To investigate the prevalence of low peripheral blood counts among HCV-infected adults in the United States general population, we analyzed data collected in the third National Health and Nutrition Examination Survey (NHANES III). The study population consisted of 16,196 individuals age 18 or older who had peripheral blood counts and data on HCV infection. The lowest fifth percentile of each component of the peripheral blood was designated a priori as being low. HCV infection was assessed by antibody reactivity. HCV antibody-positive individuals were 3-fold more likely to have low neutrophil counts (HCV positive, 9% vs. HCV negative, 3%, P <.0001) and 2.6-fold more likely to have low platelet counts (HCV positive, 13% vs. HCV negative, 5%, P <.0001) independent of other evaluated factors. HCV infection was observed in more than 20% of persons with neutrophil counts below 1.0 x 10(9)/L or platelet counts less than 100 x 10(9)/L. No association was detected between anti-HCV status and anemia or other peripheral blood cell components. In conclusion, HCV-infected persons in the general population of the United States are more likely to have low neutrophil and platelet counts, and HCV testing should be considered for persons with unexplained neutrophil counts below 1.0 x 10(9)/L or platelet counts less than 100 x 10(9)/L. Alternate causes of anemia should be considered for HCV-infected persons with low red blood cell counts.