Background: The treatment of patients with advanced cancer with multiple comorbid illnesses is complex. Although an increasing number of such patients are being referred to hospice, the comorbidity burden of this patient population is largely unknown but has implications for the complexity of care provided by hospices. This study reports the comorbidity burden in a national sample of hospice users with cancer and estimates the effect of higher comorbidity on health care use and site of death. Methods: Cross-sectional study using Surveillance, Epidemiology and End Results-Medicare data for hospice users who died of cancer in 2002 (N ¼ 27,166). We measured comorbidity burden using the Charlson comorbidity index and used multivariable generalized estimating equations to estimate the association between comorbidity burden and the following outcomes: emergency department and intensive care unit (ICU) admission, hospitalization, hospice disenrollment, and hospital death. Results: Patients with cancer who used hospice had an average Charlson comorbidity index value of 1.24, including 18.8% who suffered from comorbid dementia. In analyses adjusted for patient demographics, site of primary cancer, and number of days with hospice, higher comorbidity burden was associated with higher likelihood of emergency department admission (odds ratio [OR] ¼ 1.69, 95% confidence interval [CI] 1.52, 1.87), ICU admission (OR ¼ 3.28, 95% CI 2.45, 4.38), inpatient hospitalization (OR ¼ 2.14, 95% CI 1.90, 2.42), hospice disenrollment (OR ¼ 1.41, 95% CI 1.29, 1.56) and hospital death (OR ¼ 2.51, 95% CI 2.08, 3.02). Conclusion: These findings underscore the complexity of the hospice patient population and highlight a potential need to risk adjust the per diem hospice reimbursement rates to account for increased resource requirements for hospices serving patients with higher comorbidity burden.