Background: Thallium-201 myocardial perfusion image (MPI) is commonly used to detect coronary artery disease in patients with chest pain. Although a normal thallium-201 MPI result is generally considered to be a good prognosis and further coronary angiogram is not recommended, there are still a few patients who suffer from unexpected acute coronary events. The aim of this study was to investigate the clinical prognosis in patients with normal thallium-201 MPI. Methods: From January 2006 to August 2012, a total 22,003 patients undergoing thallium-201 MPI in one tertiary center were screened. Of these, 8092 patients had normal results and were investigated retrospectively. During follow-up, 54 patients underwent coronary angiogram because of refractory typical angina pectoris or unexpected acute coronary events. These 54 patients were divided into 2 groups: group I consisted of 26 (48.1%) patients with angiography-proven significant coronary artery stenosis, and group II consisted of 28 (51.9%) patients without significant stenosis. Results: Patients in group I had a higher prevalence of prior coronary stenting and electrocardiographic features of ST depression compared with patients in group II. The multivariate analysis demonstrated that both prior coronary stenting and ST depression were risk predictors of unexpected acute coronary events in the patients with normal thallium-201 MPI [odds ratio (OR), 5.93; 95% confidence interval (CI): 1.03-34.06, p = 0.05 and OR, 7.10; 95% CI: 1.28-39.51, p = 0.03,respectively]. Conclusions: Although there is a lowincidence of unexpected acute coronary events in patients with chest pain and normal thallium-201 MPI, physicians should be aware of the potentials risk in certain patients in this specific population.