Background. Mexico has reported high death and case fatality rates due to COVID-19. Several comorbidities have been related to mortality in COVID-19, as hypertension, diabetes, coronary heart disease, chronic obstructive lung disease and chronic kidney disease. Aims. To describe the main clinical characteristics of COVID-19 in the major social security institution in Mexico, as well as the contribution of chronic comorbidities and the population attributable fraction related to them. Methods. Data for all patients with a positive test for SARS-CoV-2 in the institutional database was included for analysis. Demographic information, the presence of pneumonia and whether the patient was hospitalized or treated at home as an outpatient as well as comorbidities were analyzed. Case fatality rate was estimated for different groups. Odds ratios with 95% confidence intervals from a logistic regression model were estimated, as well as the population attributable fraction. Results. By November 13, 2020, 323,671 subjects with COVID-19 infection have been identified. Case fatality rate is higher in males (20.2%), than in females (13.0%), and increases with age. Case fatality rate increased with the presence of obesity, hypertension and/or diabetes. Age and sex were major independent risk factors for mortality, as well as the presence of pneumonia, diabetes, hypertension, obesity, immunosuppression, and end-stage kidney disease. The population attributable fraction due to obesity in outpatients was 16.8%. Conclusions. Major cardiovascular risk factors and other comorbidities increase the risk of dying in patients with COVID-19. Identification of populations with high fatality in COVID-19, provides insight to deal with this pandemic by health services in Mexico.