To our knowledge, investigation of the trajectory of lead body burden in the U.S. based on age-period-cohort analysis has not been published. We analyzed data on red blood cell (RBC) lead as a measure of lead body burden from 76,066 National Health and Nutrition Examination Survey participants in 1976-1980, 1988-1994, and 1999-2016, who were born since 1900. Geometric means by birth decade and 5-year age group were described graphically. Using log-linear regression, RBC lead was modeled as a function of age, period, and/or birth cohort variables, entered as either discrete or continuous (transformed and/or as natural spline). A plot by birth decade and age showed that following the 1976-1980 period RBC lead had a marked decrease consistent with the well-documented decrease in blood lead. For the 1976-1980 period, preliminary regression analysis revealed that RBC lead varied by birth decade and already was decreasing at an age-dependent rate. The age-period-cohort analysis shows promise as an analytic tool for uncovering previously unrecognized patterns in time-related changes in lead body burden.