Rationale: Sepsis is a major cause of mortality among critically ill patients with cancer. Information about clinical outcomes and factors associated with increased risk of death in these patients is necessary to help physicians recognize those patients who are most likely to benefit from ICU therapy and identify possible targets for intervention. Objectives: In this study, we evaluated cancer patients with sepsis chosen from a multicenter prospective study to characterize their clinical characteristics and to identify independent risk factors associated with hospital mortality. Methods: Subgroup analysis of a multicenter prospective cohort study conducted in 28 Brazilian intensive care units (ICUs) to evaluate adult cancer patients with severe sepsis and septic shock. We used logistic regression to identify variables associated with hospital mortality. Measurements and Main Results: Of the 717 patients admitted to the participating ICUs, 268 (37%) had severe sepsis (n = 142, 53%) or septic shock (n = 126, 47%). These patients comprised the population of the present study. The mean score on the third version of the Simplified Acute Physiology Score was 62.9 6 17.7 points, and the median Sequential Organ Failure Assessment score was 9 (7–12) points. The most frequent sites of infection were the lungs (48%), intraabdominal region (25%), bloodstream as primary infection (19%), and urinary tract (17%). Half of the patients had microbiologically proven infections, and Gram-negative bacteria were the most common pathogens causing sepsis (31%). ICU and hospital mortality rates were 42% and 56%, respectively. In multivariable analysis, the number of acute organ dysfunctions (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.16–1.87), hematological malignancies (OR, 2.57; 95% CI, 1.05–6.27), performance status 2–4 (OR, 2.53; 95% CI, 1.44–4.43), and polymicrobial infections (OR, 3.74; 95% CI, 1.52–9.21) were associated with hospital mortality. Conclusions: Sepsis is a common cause of critical illness in patients with cancer and remains associated with high mortality. Variables related to underlying malignancy, sepsis severity, and characteristics of infection are associated with a grim prognosis.