We have described a simple, rapid method for determining red blood cell (RBC) life span based on measurement of alveolar carbon monoxide (CO) concentration corrected for atmospheric CO as determined with a device that simulates the body's equilibration with CO. This study was designed to determine whether direct measurements of ambient CO can be substituted for sampling with the equilibrator device. Atmospheric samplings obtained in our medical center over a period of weeks indicated that CO concentration was sufficiently constant that a single ambient CO measurement at the time of breath collection adequately corrected for atmospheric CO. Additional studies with volunteers showed that overnight CO concentrations in the subjects' home environments also remained relatively constant, suggesting that accurate assessment of RBC life span can be obtained from alveolar CO concentrations and home atmospheric samples collected on a subject's arising in the morning. Using this technique, we found that the RBC life span of 40 healthy volunteers averaged 122 ± 23 days, a value comparable to that obtained with complex cohort labeling methods. No significant correlation was observed between RBC life span and reticulocyte count in these individuals. The ability of this simple technique to detect increased RBC turnover was demonstrated in 4 subjects being treated with ribavirin and interferon for hepatitis C, a treatment reported to shorten RBC life span. Measurement of CO in samples collected by these four subjects in their home environments indicated that each had a shortened RBC life span (range 30-69 days).