Abstract Background Chest pain is the most common symptom of coronary artery disease (CAD); diabetes mellitus (DM) is a well-known single largest risk factor for cardiovascular diseases and survival worldwide. So, the impact of CAD and DM on long-term clinical effects is reported widely. This study aimed to evaluate the long-term prognostic factor for major adverse cardiac and clinical events (MACCE) in patients with chest pain without DM and CAD who underwent coronary angiography (CAG) and acetylcholine (ACH) provocation test. Methods A total of 1,046 patients with chest pain without DM and significant CAD who underwent CAG and ACH tests were finally enrolled. Propensity score matching and multivariate Cox-proportional hazard ratio analysis were performed to adjust for baseline potential confounders. All subjects were followed clinically for up to 5 years. Results Coronary spasm (CAS) seems the most common cause of chest pain. However, long-term MACCE of CAS is not worse than those of patients with chest pain without CAS when patients with CAS had subsequent optimal anti-anginal medication therapy. However, a repeated chest pain remains a problem even with continuous anti-anginal medication therapy. Up to 5-year follows, MACCE has occurred 7.3%, including recurrent angina of 6.9%. Dyslipidemia, mild to moderate CAD, and the use of aspirin/nitrates are associated with long-term MACCE. Conclusions Among the patients with chest pain without DM and significant CAD, the occurring major adverse cardiac events, including death, MI, and de novo CAD, are rare, but recurrent angina is still a challenging problem who had the treatment by anti-anginal medications.