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Background: The high incidence rate of cardiovascular (CV) events had led to a comprehensive appraisal for identifying patients who are at risk for CV disease. However, CV traditional risk factors, such as Framingham risk score (FRS), failed exhaustively to predict CV events. Methods: 402 participants (mean age, 58 [12] years; 45% male) using fingertip peripheral artery tonometry at Mayo Clinic in Rochester, Minnesota, were recruited in the present study. Measurements included reactive hyperemia index (RHI) and pain-induced peripheral artery tonometry (PIPAT). Results: After a median follow-up of 3.8 (2.7–7.7) years, 95 CV events occurred. Both first minute PIPAT and RHI were independently associated with events (hazard ratio [HR], 0.77 [95% CI, 0.61–0.98]; P = 0.038 and HR, 0.75 [95% CI, 0.59–0.96]; P = 0.019, respectively). The C statistic values of FRS, FRS + first minute PIPAT, FRS + RHI, and FRS + RHI + first minute PIPAT were 0.704, 0.722, 0.694, and 0.726, respectively. Furthermore, the addition of first minute PIPAT, RHI, and first minute PIPAT + RHI to FRS results in net reclassification improvement (NRI) in the intermediate-risk group (18.1%, P = 0.031; 18.1%, P = 0.035; 21%, P = 0.013). Conclusion: First minute PIPAT is a risk marker for adverse CV. Addition of first minute PIPAT to FRS increased the discrimination in the receiver operating characteristic analysis. It also increased NRI compared with FRS alone.