Difficulties in the laboratory measurement of protein C and protein S levels cause problems in the diagnosis of deficiency states in individual patients and may complicate estimation of the prevalence of these states in the general population. Some difficulties may be due to unappreciated influences affecting the measured levels of proteins C and S. We measured protein C activity and antigen, total and free protein S antigen, and serum total cholesterol, high-density cholesterol and triglyceride in a community-based study of 150 adults (73 male, 77 female), age range 23-80 years. Participants were identified from the list of a single general practice by stratified random sampling within sex and decade of age. Protein C activity and antigen were strongly associated with serum lipids, mean levels increasing by approximately 0.25 u/ml as total cholesterol and triglyceride concentration each rose from the 5th to 95th centile. Total protein S antigen concentration was associated with total cholesterol, the mean rising by over 0.1 u/ml as total cholesterol increased from the 5th to the 95th centile, whilst a similar rise in triglyceride was associated with an increase in mean free protein S of more than 0.3 u/ml. Overall, physiological variation in total cholesterol and triglyceride concentration was associated with significant variation in protein C and protein S levels, independent of age and sex, suggesting that it is important to take serum lipids into account when investigating patients for protein C or protein S deficiency. Failure to do so may be misleading in some circumstances.