The association of smoking low yield cigarettes with the risk of cancer, cardiovascular disease, and other disease associated previously with smoking is controversial. In 1979 we began a prospective epidemiologic study of this subject. We here report on the first 4 years of follow-up in the 16,270 current, regular cigarette smokers and the 42,113 subjects who never used any form of tobacco enrolled in the study. In multivariate analyses that included age, sex, race, number of cigarettes smoked per day and other factors related to cardiovascular disease, the risk of cardiovascular diseases was consistently higher in smokers of higher than in smokers of lower yield cigarettes, although the magnitude of the difference in risk was very small. The risks of cancer of the trachea, bronchus and lung, of all smoking-related cancers as a group, of diseases of the respiratory system, and of peptic ulcer diseases were not significantly associated with yield in smokers. The incidence rates of cardiovascular diseases considered as a group, cancer of the trachea, bronchus, and lung and all smoking-related cancers were higher in smokers of low yield cigarettes than in never users of any form of tobacco. We conclude that the smoking of low yield cigarettes is not without associated hazard. On the other hand, the results suggest that smokers who cannot quit might best use the least number of the lowest yield cigarette.