Background <p>The obesity paradox, where higher body mass index (BMI) is associated with improved survival, is observed in sepsis and cancer individually. However, its effect in patients with both conditions is unclear. The objective of this study is to evaluate the obesity paradox in intensive care unit (ICU) patients with sepsis and cancer and examine whether BMI’s impact on mortality varies across patient phenotypes.</p> Methods <p>Data from the Medical Information Mart for Intensive Care IV database were analyzed. Patients were categorized by BMI into underweight (&lt;18.5 kg/m², <i>n</i> = 173), normal weight (18.5–24.9 kg/m², <i>n</i> = 1283), overweight (25–29.9 kg/m², <i>n</i> = 1498), and obesity (≥30 kg/m², <i>n</i> = 960). The primary outcome was 28-day mortality, with secondary outcomes including 6-month mortality, 1-year mortality, length of ICU stay, continuous renal replacement therapy usage, and invasive ventilation usage. Multivariable logistic regression and restricted cubic splines were used to explore the BMI-mortality relationship, and unsupervised clustering was performed to identify patient phenotypes.</p> Results <p>Among 3914 patients, obesity was associated with lower mortality. Clustering revealed four distinct phenotypes, with the protective effect of obesity being more evident in patients with lower Sequential Organ Failure Assessment (SOFA) scores (Cluster1, Cluster2 and Cluster3).</p> Conclusions <p>The obesity paradox is evident in both short-term outcome (28-day mortality) and long-term outcomes (6-month and 1-year mortality) among patients with sepsis and cancer, particularly in those presenting with lower disease severity. These findings highlight the need for personalized treatment approaches in this complex patient population.</p>