Objectives: To describe risk factors for mortality and clinical characteristics in patients with mpox infection at a reference hospital in Mexico. Design: A prospective cohort study was conducted from September to December 2022 at Hospital de Infectología La Raza National Medical Center. Methods: Study participants were patients that met operational definition of confirmed case of mpox according to WHO criteria. Information was obtained through a case report form that included epidemiological, clinical, and biochemical information. The follow-up period was from initial evaluation for hospitalization until discharge due to clinical improvement or death. Written informed consent was obtained from all participants. Results: Seventy-two patients were included in the analysis, 64 of 72 (88.9%) were people with HIV (PWH). Of the total of patients 71 of 72 (98.6%) were male, with a median age of 32 years old [95% confidence interval (CI), interquartile range (IQR) 27-37]. Coinfection with sexually transmitted infections was reported in 30 of 72 (41.7%). The overall mortality was five of 72 (6.9%). The incidence of mortality rate in PWH was 6.3%. Median days from onset of symptoms to death from any cause during hospitalization was 50 days (95% CI, IQR 38-62). Risk factors for mpox mortality in the bivariate analysis were CD4 + cells count ≤100 cells/μl at the time of assessment RR 20 (95% CI, IQR 6.6-60.2) ( P < 0.001), absence of antiretroviral therapy RR 6.6 (95% CI, IQR 3.6-12.1) ( P = 0.001) and ≥50 skin lesions at presentation RR 6.4 (95% CI, IQR 2.6-15.7) ( P = 0.011). Conclusions: The clinical presentation between PWH and non-HIV patients was similar in this study, however, reported mortality was associated with advanced-HIV disease.