Purpose – The study was conducted to examine whether use of cimetidine is associated with the risk of cancer, with special attention to cancers of the breast and prostate because cimetidine increases estradiol levels and interferes with androgen binding. Methods – Individuals who received a prescription of cimetidine were identified from two computerized pharmacy databases of medications dispensed at Northern California Kaiser Permanente between 1982 and 1987. Users of ranitidine, a histamine-2 receptor antagonist that does not appear to influence estrogen levels or androgen binding, and non-users of either cimetidine or ranitidine, were also identified from these databases. Study subjects were followed through December 1995 for new diagnoses of cancer. Cox regression was used to estimate relative risks of cancer associated with use of cimetidine and ranitidine. Non-users of cimetidine and ranitidine were the referent group for all analyses. Result – While there were very modest increases and decreases in risk for some cancer sites among cimetidine users, most were within the limits of chance given no true association. Furthermore, similar risks of these cancers were also observed among ranitidine users. Conclusions – Although our results do not support an association between cancer risk and cimetidine use, it is one of the most widely prescribed drugs in the US and may now be purchased over-the-counter. The potential effect of cimetidine on risk of cancer, especially those that are hormone-related, should continue to be monitored, preferably in larger study populations. Copyright (c) 2000 John Wiley & Sons, Ltd.