The inflammatory response associated with COVID-19 varies with sex, potentially affecting disease outcomes. Males have a higher risk of complications compared to females, requiring an evaluation of differences in inflammatory response severity based on sex. To compare clinical data, biochemical biomarkers, and outcomes among hospitalized COVID-19 patients in Latin America and the Caribbean (LA&C) based on sex and to perform a cluster analysis of biomarker profiles for both sexes. This prospective, multicenter observational registry made by the Inter-American Council of Heart Failure and Pulmonary Hypertension of the Inter-American Society of Cardiology included hospitalized COVID-19 patients from 44 hospitals in 14 countries in LA&C between May 1, 2020, and June 30, 2021. Of 3,260 patients (1,201 females and 2,059 males), males had higher C-reactive protein and ferritin levels, while females had higher natriuretic peptides and d-dimer levels. Males had more cardiovascular complications (acute coronary syndrome [3.3% vs. 2.2%], decompensated heart failure [8.9% vs. 7.8%], pulmonary embolism [4.4% vs. 2.9%]), intensive care unit (ICU) admissions (56.9% vs. 47.7%), and overall mortality (27.5% vs. 22.1%). Cluster analysis identified three groups: one with normal-range biomarkers but elevated ferritin, one with coagulation abnormalities, and one with an inflammatory profile linked to renal injury and increased non-cardiovascular mortality. In the LA&C population hospitalized with COVID-19, males had higher inflammatory biomarker levels, correlating with increased cardiovascular complications and mortality. The cluster with an inflammatory profile showed higher non-cardiovascular mortality, while clusters with elevated ferritin levels were associated with increased ICU admissions.