We investigated the relationship between level of exercise, ingestion of zinc supplements, and serum high-density lipoprotein (HDL) cholesterol levels in 270 healthy men and women over age 60. After controlling for sex, alcohol intake, and body mass, there was a significant positive correlation between level of exercise and serum HDL cholesterol in the 180 subjects not taking supplemental zinc (r = 0.26, P = .005) but not for those subjects taking supplemental zinc (r = -0.18, P = .14). Multiple regression analysis showed a significant interaction of zinc intake and activity level on HDL cholesterol (P = .04). In 22 subjects who were ingesting greater than 15 mg of supplemental, elemental zinc daily, cessation of zinc supplements for 8 weeks was associated with a significant increase in HDL cholesterol levels (2.0 mg/dL; P = .04). The change in HDL after stopping zinc was positively correlated with the level of exercise of the subjects (r = .41, P = .05). Thus supplemental zinc ingestion appears to block the exercise-induced increase in serum HDL cholesterol in a healthy population.