Few studies have focused on sepsis in patients with pre-existing immunosuppression. Since the numbers and the incidence of sepsis are increasing, sepsis in immunosuppressed patients will increase in importance. We studied the epidemiology of sepsis and risk factors for 28-d mortality in patients immunosuppressed prior to the onset of sepsis using data from the Academic Medical Center Consortium's (AMCC) prospective observational cohort study of sepsis. We compared characteristics of immunosuppressed (n =412) and immunocompetent (n =754) patients. Immunosuppressed patients were younger and more likely to have underlying liver or lung disease, and nosocomial infection or bloodstream infection of unknown source when presenting with sepsis. They were also more likely to die within 28 d compared to immunocompetent patients (adjusted relative risk 1.62, 95% CI 1.38 - 1.91). Septic shock, hypothermia, cancer and invasive fungal infections were associated with increased mortality in immunosuppressed patients. Black race and the presence of rigors were independent predictors of survival in immunosuppressed patients. We conclude that sepsis among patients immunosuppressed prior to the onset of sepsis was associated with higher mortality than in immunocompetent patients. As the numbers of immunosuppressed patients continue to grow, more studies on the epidemiology of sepsis in this group will become increasingly important.