This study tested the hypothesis that skeletal muscle mass is reduced in elderly women and men after adjustment first for stature and body weight. The hypothesis was evaluated by estimating appendicular skeletal muscle mass with dual-energy X-ray absorptiometry in a healthy adult cohort. A second purpose was to test the hypothesis that whole body 40K counting-derived total body potassium (TBK) is a reliable indirect measure of skeletal muscle mass. The independent effects on both appendicular skeletal muscle and TBK of gender (n = 148 women and 136 men) and ethnicity (n = 152 African-Americans and 132 Caucasians) were also explored. Main findings were 1) for both appendicular skeletal muscle mass (total, leg, and arm) and TBK, age was an independent determinant after adjustment first by stepwise multiple regression for stature and weight (multiple regression model r2 = approximately 0.60); absolute decrease with greater age in men was almost double that in women; significantly larger absolute amounts were observed in men and African-Americans after adjustment first for stature, weight, and age; and >80% of within-gender or -ethnic group between-individual component variation was explained by stature, weight, age, gender, and ethnicity differences; and 2) most of between-individual TBK variation could be explained by total appendicular skeletal muscle (r2 = 0.865), whereas age, gender, and ethnicity were small but significant additional covariates (total r2 = 0.903). Our study supports the hypotheses that skeletal muscle is reduced in the elderly and that TBK provides a reasonable indirect assessment of skeletal muscle mass. These findings provide a foundation for investigating skeletal muscle mass in a wide range of health-related conditions.