Conflicting reports on the effect of smoking and coffee drinking on lipoproteins prompted us to study the combined effect of these two associated, widely prevalent habits in 361 persons randomly sampled from the Evans County cohort. Low-density lipoprotein (LDL) cholesterol levels were significantly higher among persons who smoked cigarettes and consumed five or more cups of coffee per day than among nonsmokers who abstained from coffee. Conversely, high-density lipoprotein (HDL) cholesterol was higher in persons who did not smoke or drink coffee than in coffee-consuming smokers. However, this trend was not statistically significant. Triglycerides and very low-density lipoprotein (VLDL) cholesterol were highest among smokers who drank five or more cups of coffee per day, but these differences did not reach statistical significance. Lipoprotein cholesterol levels were adjusted for age, sex and body mass. Smoking and coffee drinking interact in affecting LDL and total cholesterol, but coffee drinking alone did not appear to affect blood lipids.