To ascertain the impact of minor illness on total plasma cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), we analyzed data collected on 6,880 persons examined for the Stanford Five-City Project. Overall, 8.4% of the population reported having a minor illness on the day of examination, although there were substantial variations in minor illness rates with season, city, and year of data collection. After adjustment for age, sex, body mass index, season, and city of residence, we found that those who reported minor illness at the time of examination had a lower mean TC than those who were well (195.9 mg/dL versus 201.2 mg/dL, P less than .005). HDL-C was 51.2 mg/dL in persons with minor illness, and 52.3 mg/dL in persons without (P = .13). Dietary recall data covering the 24-hour period before the examination was available on a subset of the patients. No dietary differences appeared between individuals who reported minor illness and those who did not. In a subset of 162 persons with a minor illness who were followed longitudinally for up to six years, TC adjusted for age was 191.8 mg/dL with minor illness and 196.1 mg/dL without, a difference that was not statistically significant. The results of this study imply that minor illness may contribute to some of the biological variability of TC and HDL-C. Although small, a differential rate of minor illness may sometimes significantly affect interpretation of TC epidemiological and intervention studies or the timing of measurements in clinical practice.