Evidence exists that increased levels of physical activity decrease the population burden of cardiovascular disease (CVD). Although risk factors for CVD, including plasma lipids and lipoproteins, have been associated with physical activity, studies including a sizeable number of minority participants are lacking. Our purpose was to interrogate the longitudinal effect of physical activity on plasma lipids and lipoproteins in the African American and white participants of the Atherosclerosis Risk in Communities (ARIC) Study. Nine years of follow-up data on 8,764 individuals aged 45-64 years at baseline were used in linear mixed-effects models to estimate the association between increases in baseline physical activity on mean change in HDL, LDL, total cholesterol, and triglyceride levels. Increases in the level of activity were associated with increases in HDL in all strata and decreases in triglycerides among white participants. Physical activity was associated with LDL in all women, while the association with total cholesterol was limited to African American women. This study is one of the few to investigate the effect of physical activity on lipids and lipoproteins in a race- and sex-specific manner. Overall our results highlight the importance of physical activity on plasma lipid profiles and provide evidence for novel differential associations.