Background: The cancer research groups of the National Cancer Institute's National Clinical Trials Network have a history of successful conduct of large randomized phase III trials of chemoprevention for cancer. An important question for funding agencies is whether the conduct of large chemoprevention trials provides strong scientific return on investment. Methods: We evaluated the scientific impact of four large chemoprevention trials – two for breast cancer and two for prostate cancer – using citation analysis, a bibliometric technique. The results were compared to the scientific impact of a series of treatment trials conducted over the same 20-year time period (1991–2010, inclusive). Average annual citation counts were compared using t-tests. Scientific impact was also assessed relative to trial costs. Results: Twenty-seven treatment trials with 17,208 patients and four chemoprevention trials with 87,550 patients were examined. The mean annual citation rate for primary articles was higher for chemoprevention trials compared to treatment trials (188.1 vs. 40.4, p =.001). For both primary and secondary article publications, mean annual citations for articles associated with chemoprevention trials were also higher (483.9 vs. 69.0, p =.0003). Large chemoprevention trials were estimated to provide 50% more total citations from primary and secondary articles on a cost-adjusted basis. Conclusion: Based on these criteria, the scientific impact of large phase III cancer chemoprevention trials was very high in absolute terms, and as good as or better than that of treatment trials after accounting for expenditure. For appropriate scientific questions, large chemoprevention trials provide a good scientific return on investment for federal funding agencies.