Objective: In this study, we aimed to evaluate the accuracy of the original and simplified pulmonary embolism (PE) severity index (PESI) to predict all-cause mortality after 30 days of acute PE diagnosis up to five years within consecutive sub-periods. Methods: Adult patients diagnosed with acute PE between January 1, 2003, and June 30, 2013, were retrospectively included. Data on baseline characteristics and mortality during a five-year follow-up were collected. Results: The study included 414 patients (Male/Female=192/222). The median age at diagnosis was 61.5 (minimum–maximum, 18–93) years. Mortality rates were 13.3% at 30 days, 21.8% at 90 days, 32.6% at one year, and 51.0% at five years. Both stratification into risk classes according to the original PESI and low vs. high-risk classification of original and simplified PESI were significantly correlated with the 30-day, 31-90- day, 91-day-one-year, and one-five-year mortality. Significant PESI predictors for mortality were history of cancer [hazard ratio (HR): 3.31, 95% confidence interval (CI): 1.64-6.68; p=0.001] and heart failure (HR: 2.35, 95% CI: 1.04-5.32, p=0.041) at 31-90-day, history of cancer (HR: 5.45, 95% CI: 2.86-10.40, p<0.001) at 91-day-one-year, advancing age (HR: 1.04, 95% CI: 1.02-1.06, p<0.001) and history of cancer (HR: 5.53, 95% CI: 3.41-8.98, p<0.001) at one-five-year after acute PE diagnosis. Conclusion: All-cause long-term mortality in high-risk patients with acute PE according to original or simplified PESI significantly increased up to five years of follow-up. This survival disadvantage was mainly related to cancer and comorbidities rather than acute clinical manifestations. Future prospective studies are needed to demonstrate the effect of various comorbidities on long-term mortality in these patients