To identify factors associated with the risk of death in adolescent and adult inpatients with laboratory-positive (reverse-transcription polymerase chain reaction) influenza in Mexico during consecutive influenza seasons (2018-2020).A retrospective cohort study used national surveillance system data, enrolling 3422 individuals. The association between various risk factors and 30-day in-hospital lethality were evaluated through risk ratios (RR) and 95% confidence intervals (CI).The lethality rate was 18.1%. Flu vaccination history (RR = 0.56, 95% CI 0.42-0.78), early antiviral drug administration (≤ two days from symptom onset [reference ≥ 5 days], RR = 0.68, 95% CI 0.58-0.81), and a history of asthma (RR = 0.66, 95% CI 0.47-0.95) showed protective effects against influenza-attributable death. Mechanical ventilator support produced the highest increase in death risk (RR = 3.31, 95% CI 2.89-3.79). Male sex, older age, AH1N1 subtype, and other chronic diseases were also associated with fatal in-hospital influenza-related outcomes.Our findings highlight the major relevance of promoting immunization in high-risk individuals, together with ensuring early and effective antiviral management in suspected influenza cases.Copyright © 2020 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.