The effects of long-term supplementation with pharmacologic doses of zinc oxide on serum levels of zinc, lipids and hematocrit have not been studied systematically to date. Eleven Clinical Centers enrolled 4757 participants from 1992 to 1998 as part of the Age-Related Eye Disease Study (AREDS). Of these, 3640 participants, aged 55-80 y, who had early-to-late age-related macular degeneration (AMD) were randomly assigned to daily supplementation with or without 80 mg of zinc as zinc oxide plus 2 mg of copper as cupric oxide to study the effects of zinc supplementation on the progression to late AMD. This paper reports on the effect of a 5-y supplementation with zinc oxide and cupric oxide on serum zinc, copper, lipids, and hematocrit for 717 participants from three clinical centers. At the 5-y exam, the median increase in serum zinc levels for participants assigned to zinc formulations was 17% compared with a 2% increase for participants not assigned to zinc (P < 0.001). The differential effect on serum zinc was observed at 1 y and remained fairly constant over the 5-y period. After 5 y, no significant differences in changes in serum hematocrit, copper or lipids were found between participants assigned to formulations containing zinc and copper, and those assigned to formulations without zinc and copper. Estimates from a modified Block Food-Frequency Questionnaire suggest the AREDS population at baseline had a zinc intake from diet similar to that of the general population.