Introduction: Although lipid profiles tend to worsen with age, it is not fully known if such age-related changes are influenced primarily by body composition and lifestyle or by other aspects of aging. Objective: We investigated the extent to which the fat and fat-free components of body mass index (BMI) and lifestyle factors influence patterns of change in lipids independent of age. Design: Serial data were analyzed using sex-specific longitudinal models. These models use serial data from individuals to assume a general pattern of change over time, while allowing baseline age and the rate of change to vary among individuals. Subjects: Serial data were obtained from 940 examinations of 269 healthy white participants (126 men, 143 women), aged 40–60 years, in the Fels Longitudinal Study. Measurements: Measurements included age, the fat (FMI) and fat-free mass (FFMI) components of BMI, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), triglycerides (TG), total cholesterol (TC), fasting glucose and insulin, physical activity, alcohol use and smoking, and women's menopausal status and estrogen use. Results: In both sexes, increased FMI was significantly associated with increased LDL-C, TG and TC, and decreased HDL-C. Increased FFMI was significantly related to decreased HDL-C and increased TG. Independent age effects remained significant only for LDL-C and TC in men and TC in women. Increased insulin was significantly related to increased TG in women. Moderate alcohol consumption was associated with higher HDL-C in men. Physical activity lowered male LDL-C and TC levels, and increased female HDL-C levels. Menopause was associated with increases in LDL-C. Premenopausal women not using estrogen had significantly lower HDL-C, TG, and TC than postmenopausal women taking estrogen. Conclusions: (1) Age is an important independent predictor for LDL-C and TC in men, and TC in women, but it is not as influential as body composition and lifestyle on HDL-C and TG in men and women, and LDL-C in women. (2) Increasing FMI is the major contributor to elevated TC, LDL-C and TG levels, and decreased HDL-C levels in men and women. (3) FFMI significantly influences HDL and TG levels in both sexes. (4) Maintaining a lower BMI via a reduced fat component may be more beneficial in lowering CVD risks than other factors.