Underlying disorders, especially those that chronically impair immune host response (e.g., cancers and hematologic malignancies) but also those that acutely impair this response (e.g., major surgery and multiple trauma), increase the incidence of infection and alter the outcome of patients with sepsis. As a part of innate immunity, inflammatory and coagulation responses are lower in patients with underlying disorders than in patients without such disorders, whereas the need for vasopressors and mechanical ventilation is more frequent. Although these patients are older, age-related defects do not appear to be responsible for this lower response, because innate immunity is usually up-regulated in the elderly. Innate immunity seems to be negligibly affected by the direct consequences of underlying disorders, but underlying disorder-related chronic organ insufficiency certainly participates in the observed organ dysfunction, overestimating the infectious insult by itself. Although innate immunity seems not to be actually blunted in patients with underlying disorders, the underlying disorder itself contributes to the severity of the physiological response to sepsis, thereby resulting in a worse outcome.