Racial and gender differences in single-breath pulmonary diffusing capacity for carbon monoxide (DLCO) have previously received little attention. Between 1971 and 1975, the first National Health and Nutrition Examination Survey determined DLCO for 4,439 adults ages 25 to 74 residing in the United States, including 2,345 women and 438 blacks. The large sample permitted an evaluation of interactions and nonlinear relationships with DLCO, and its association with biomarkers of inflammation. In a model with separate race, sex, and smoking status intercepts, positive associations with FVC, height, weight, hemoglobin concentration, and negative associations with age and neutrophil count explained 59% of the variation in DLCO. In women, the decline in DLCO with age was much less than in men, but after age 47 the decline with age approached that seen in men. Blacks had lower DLCO levels (-1.96 ml/min/mm Hg, 95% confidence interval [CI] -0.77 to -3.14) with or without adjustment for FVC, but the changes in DLCO with age and height were similar in both races. Former smokers had lower DLCO (-1.13 ml/min/mm Hg, 95% CI -1.57 to -0.69), but this reduction was fully explained by the number of pack-years smoked. In current smokers, cigarettes per day and pack-years were predictive of DLCO even after control for FVC and controlling for these variables fully explained the difference in DLCO between never and current smokers. Peripheral neutrophil count, a biomarker of inflammation, was associated with reduced DLCO. Thus, substantial sex and race differences exist for DLCO within the general United States population.