Background: CCI is an established tool used to measure the comorbidity burden in patients, with higher CCI signifying a greater comorbidity burden. We performed a large database analysis to evaluate CCI as a predictor of one-month mortality and OS in patients < 60 years with APL. Methods: Using the National Cancer Database, we identified a total of 4969 patients < 60 years diagnosed with APL between 2004 and 2015. We divided patients into 3 groups with CCI of 0, 1, and ≥2. Multiple regression analysis was used to evaluate the effects of CCI on one-month mortality. Cox regression model determined the impact of CCI on OS. Results: Seventy-eight percent of patients had CCI of 0; 16% had CCI 1, and 6% had CCI ≥2. Median age was 42 years (range 0-59), and patients 41-59 years comprised 53% of the total cohort. Fifty-one percent were female, 32% were treated at academic centers, and 67% had private insurance. One-month mortality was 5%, 14%, and 25% for patients with CCI 0, 1 and ≥2, respectively. After adjusting for other co-variates, one-month mortality was worse for patients with CCI 1 (Odds ratio 2.6, 95% confidence interval [CI] 2.0-3.4, p < 0.001) and CCI ≥2 (Odds ratio 5.3, 95% CI 3.9-7.4, p < 0.001) compared to patients with CCI 0. Median 5-year OS was 85%, 71%, and 60% for patients with CCI 0, 1, and ≥2, respectively. After adjusting for other co-variates, OS was worse for patients with CCI 1 (Hazard ratio [HR] 1.8, 95% CI 1.5-2.1, p < 0.001), and CCI ≥2 (HR 2.7, 95% CI 2.2-3.3, p < 0.001) compared to patients with CCI 0. Patients 41-59 years had worse OS than 0-18 years (HR 2.4, 95% CI 1.3-4.5, p = 0.003). Private insurance was associated with better OS than Medicare (HR 2.1, 95% CI 1.7-2.6, p < 0.001) and Medicaid/other government insurance (HR 1.3, 95% CI 1.1-1.6, p < 0.001). Conclusions: This is one of the first and the largest database analyses examining the prognostic association of comorbidity burden in younger patients with APL. CCI independently predicted both one-month mortality and OS. Compared to CCI of 0, one-month mortality increased by 2.5-fold with CCI 1 and more than five-fold with CCI ≥2. The higher chances of one-month mortality in patients with greater comorbidity burden may reflect the risks associated with initial APL diagnosis and treatment such as coagulopathy, infection, and differentiation syndrome. One-month mortality was the key driver for OS. OS was also worse among patients with higher CCI. Our results indicate CCI as an important predictor of one-month mortality and OS in APL. CCI should be taken into consideration while interpreting clinical trial results.