Purpose: This study examines how the information provided by a diagnostic decision support system for clinical cases of varying diagnostic difficulty affects physicians' diagnostic performance. Methods: A national sample of 67 internists, 35 family physicians, and 6 other physicians used the Quick Medical Reference (QMR) diagnostic decision support system to assist them in the diagnosis of written clinical cases. Three sets of eight cases, stratified by diagnostic difficulty and the potential of QMR to produce high-quality information, were used. The effects of using QMR on three measures of physicians' diagnostic performance were analyzed using analyses of variance. Results: Physicians' diagnostic performance was significantly higher (p < 0.01) on the easier cases and the cases for which QMR could provide higher-quality information. Conclusions: Physicians' diagnostic performance can be strongly influenced by the quality of information the system produces and the type of cases on which the system is used.