Background: We examined whether CERT1 score (a plasma ceramide-based risk score) is associated with an increased risk of overall mortality and adverse cardiovascular events in patients with and without known cardiovascular disease. Methods: For the calculation of the CERT1 score, we measured three specific plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0) and Cer(d18:1/24:1)] and their ratios to Cer(d18:1/24:0) in 530 patients with and without cardiovascular disease, who were followed for a median of 74 months (interquartile range 54-79 months). The primary study outcome was a composite of all-cause mortality or incident nonfatal myocardial infarction, ischemic stroke, and atrial fibrillation. Results: A total of 139 total deaths or nonfatal cardiovascular events occurred over the follow-up. There was a significant association across baseline CERT1 risk categories (low, moderate, increased, and high risk) and the risk of developing the primary composite outcome (unadjusted hazard ratio [HR] for high vs. low-risk category: 2.63, 95% confidence interval [CI] 1.57-4.43; unadjusted HR for increased vs. low-risk category: 2.42, 95% CI 1.47-3.96, p<0.0005). This risk remained significant even after adjusting for age, sex, smoking, hypertension, obesity, diabetes, chronic kidney disease, prior history of cardiovascular disease, and use of anti-platelet or statin medications (adjusted-HR for high vs. low-risk category: 2.43, 95% CI 1.39-4.22, p=0.002; adjusted-HR for increased vs. low-risk category: 2.16, 95% CI 1.28-3.63, p=0.004). Conclusions: The ceramide-based risk score CERT1 is independently associated with an increased long-term risk of overall mortality and adverse cardiovascular outcomes in patients with and without known cardiovascular disease