It remains uncertain whether factors other than the severity of coronary artery disease (CAD) are associated with the worsening of the left ventricular ejection fraction (LVEF) by exercise. In the present study the impact of coronary risk factors on the worsening of LVEF by exercise was investigated in 391 patients with known or suspected CAD using exercise-gated (201)Tl scanning to calculate the LVEF. Significant worsening of the LVEF by exercise was defined as >4.7% (mean plus 1 SD of the value in 116 patients without CAD). Multivariate analysis revealed that diabetes mellitus (DM) was an independent risk factor for the worsening of LVEF by exercise in patients with multivessel (2- or 3-vessel) CAD with an odds ratio (95% confidence interval) of 2.2 (1.1-4.5, p=0.037). In 157 patients with 2- or 3-vessel CAD, 20 (23.5%) of 85 nondiabetic patients and 31 (43.1%, p=0.009 vs nondiabetic patients) of 72 diabetic patients showed significant worsening of LVEF by exercise. In patients with 2- or 3-vessel CAD, there was no significant difference in Gensini score or reversibility of perfusion defects between nondiabetic and diabetic patients. Thus, DM is a risk factor for worsening LVEF by exercise in addition to the severity of CAD.