Hospitalized adult patients with cancer and with major comorbidities have higher mortality rates and longer duration of hospitalization. There is limited understanding of risk factors that contribute to prolonged hospitalization and mortality in older patients with solid tumors. Risk factors associated with in-hospital mortality and prolonged length of stay (LOS) in older patients with cancer were investigated in a retrospective cohort study. Data from the University HealthSystem Consortium database included 386,377 patients age ≥ 65 years with solid tumors hospitalized between 1995 and 2003 at 133 U.S. academic medical centers. The overall mortality rate was 7.3%. Mortality in older patients with cancer was strongly associated with longer LOS. Almost twice as many deaths were observed among those with LOS ≥ 10 days (p<0.0001). Nearly 38% of older cancer patients who died in hospital had potentially curable disease. Primary central nervous system malignancies were most strongly associated with in-hospital mortality (OR=1.81; 1.59-2.07), followed by esophageal (OR=1.74; 1.54-1.97) and lung cancer (OR=1.57; 1.43-1.72). Male gender, African-American race, and Hispanic and Asian race/ethnicity were associated with increased risk of mortality (p<0.0001). Additional risk factors included metastatic disease, infection, neutropenia, renal, lung, hepatic, cerebrovascular disease, arterial/venous thromboembolism, heart failure, and red blood cell transfusion. Risk factors for prolonged LOS included gastric cancer, infection, venous thromboembolism and red blood cell transfusion. Prolonged LOS was strongly associated with mortality. Risk factors such as infection, neutropenia and red blood cell transfusion, when modified, could potentially reduce rates of prolonged LOS and mortality in older patients with cancer.