Dengue patients with comorbidities may be at higher risk of death. In this cross-sectional study, healthcare databases from Mexico (2008-2014), Brazil (2008-2015), and Colombia (2009-2017) were used to identify hospitalized dengue cases and their comorbidities. Case fatality rates (CFRs), relative risk, and odds ratios (OR) for in-hospital mortality were determined. Overall, 678,836 hospitalized dengue cases were identified: 68,194 from Mexico, 532,821 from Brazil, and 77,821 from Colombia. Of these, 35%, 5%, and 18% were severe dengue, respectively. Severe dengue and age ≥ 46 years were associated with increased risk of in-hospital mortality. Comorbidities were identified in 8%, 1%, and 4% of cases in Mexico, Brazil, and Colombia, respectively. Comorbidities increased hospitalized dengue CFRs 3- to 17-fold; CFRs were higher with comorbidities regardless of dengue severity or age. The odds of in-hospital mortality were significantly higher in those with pulmonary disorders (11.6 [95% CI 7.4-18.2], 12.7 [95% CI 9.3-17.5], and 8.0 [95% CI 4.9-13.1] in Mexico, Brazil, and Colombia, respectively), ischemic heart disease (23.0 [95% CI 6.6-79.6], 5.9 [95% CI 1.4-24.6], and 7.0 [95% CI 1.9-25.5]), and renal disease/failure (8.3 [95% CI 4.8-14.2], 8.0 [95% CI 4.5-14.4], and 9.3 [95% CI 3.1-28.0]) across the three countries; the odds of in-hospital mortality from dengue with comorbidities was at least equivalent or higher than severe dengue alone (4.5 [95% CI 3.4-6.1], 9.6 [95% CI 8.6-10.6], and 9.0 [95% CI 6.8-12.0). In conclusion, the risk of death because of dengue increases with comorbidities independently of age and/or disease severity.