We examined the decline in high-density lipoprotein cholesterol in adolescent males and the postadolescent sex differences in HDL cholesterol levels. Prevalence data are presented for 1639 white males and females ages 6-25 years from six populations of the Lipid Research Clinics Program. The association of HDL cholesterol with age, smoking habits, and anthropometric, clinical chemistry and nutritional variables was examined by correlation and regression analyses. Although mean HDL cholesterol levels in children ages 6-10 years were lower in females than in males, HDL cholesterol levels gradually increased with age in females, while in males the mean HDL cholesterol levels declined form 55.9 mg/dl at ages 6-10 years to 45.5 mg/dl at ages 18-25 years. In young adults, HDL cholesterol levels were an average of 10.5 mg/dl higher in females than in males. In the 6-10-year-old age group, none of the study variables was significantly associated with HDL cholesterol. In the 11-17-year-old subjects, significant associations were noted with several variables, especially in the males. The strongest association was an inverse association with weight in males. In the young adults ages 18-25 years, significant inverse associations were found with weight and alkaline phosphatase in both sexes and with sucrose and smoking in females. The data suggested that the most important influence on HDL cholesterol levels in adolescent males are changes in gonadal hormone levels and that some of the factors known to influence HDL cholesterol levels in older adults are already associated with HDL cholesterol in adolescents and young adults.