We previously reported that change, with age, in plasma levels of total cholesterol (TC) and LDL cholesterol (LDL-C) differed between apolipoprotein E (APOE) genotypes e3e3 and e3e4, in a sample of 77 older, unrelated males. By use of a larger sample from that cohort, followed longitudinally during 1969–87, the change in TC and in LDL-C, between the e3e3 and e3e4 APOE genotypes, over three exams, was reanalyzed. Additionally, the change in triglycerides (TG) and in HDL-choles-terol (HDL-C), between the e3e3 and e3e4 APOE genotypes—as well as the differences between the e3e3 and e3e2 genotypes, for TC, LDL-C, TG, and HDL-C—were contrasted over the three exams. At exam 1 TG was higher in the e3e4 group than in the e3e3 group (mean age 48 years), and at exams 2 and exam 3 (mean ages 58 and 63 years, respectively) it was similar (P = .009 for the exam-by-genotype-interaction effect in the repeated-measures analysis). A similar trend was seen for TC (P = .03), yet previously detected LDL-C effects were not apparent (P = .46). Those with the e3e2 genotype had higher TG and lower LDL-C and TC at each exam than were seen in those with the e3e3 genotype, although the differences in the values were not always statistically significant. Differences in TC, LDL-C, and TG, between the e3e2-genotype and e3e3-genotype groups, did not significantly change over the three exams. HDL-C levels were relatively stable over the exams; however, the exam-by-genotype interaction was significant for the e3e2 genotype versus the e3e3 genotype (P = .02). The e4 allele effects on TG and TC changed between longitudinal exams and may be age dependent. Changes, with age, in the effect of the e3e4 genotype on lipids may impact the risk of developing atherosclerotic disease.