BACKGROUND: Inpatient hospital stays account for more than a third of direct medical cancer care costs. Evidence on factors driving these costs can inform planning of services, as well as consideration of equity in access. OBJECTIVE: To measure the association between hospital costs, and demographic, clinical, and system factors, for a cohort of adults with advanced cancer. DESIGN: Prospective multisite cohort study. SETTING: Four medical and cancer centers. PATIENTS: Adults with advanced cancer admitted to a participating hospital between 2007 and 2011, excluding those with dementia. Final analytic sample included 1020 patients. METHODS: With receipt of palliative care controlled for, the associations between hospital cost and patient factors were estimated. Factors covered the domains of demographics (age, sex, race), socioeconomics and systems (education, insurance, living will, proxy), clinical care (diagnoses, complications deemed to pose a threat to life or bodily functions, comorbidities, symptom burden, activities of daily living), and prior healthcare utilization (home help, analgesic prescribing). OUTCOME MEASURE: Direct hospital costs. RESULTS: A major (markedly abnormal) complication (+$8267; P < 0.01), a minor but not a major complication (+$5289; P < 0.01), and number of comorbidities (+$852; P < 0.01) were associated with higher cost, and admitting diagnosis of electrolyte disorders (–$4759; P = 0.01) and increased age (–$53; P = 0.03) were associated with lower cost. CONCLUSIONS: Complications and comorbidity burden drive inhospital utilization for adults with advanced cancer. There is little evidence of sociodemographic associations and no apparent impact of advance directives. Attempts to control growth of hospital cancer costs require consideration of how the most resource-intensive patients are identified promptly and prioritized for cost-effective care.