OBJECTIVES: To compare cancer care spending and utilization by site of provider-administered chemotherapy in Medicare. STUDY DESIGN: A retrospective analysis using 2010-2013 Medicare claims. METHODS: The study population was a random sample of Medicare fee-for-service beneficiaries with cancer who initiated provider-administered chemotherapy in a hospital outpatient department (HOPDI or physician office (PO). We assessed the following outcomes during the 6-month follow-up period: (1) spending on cancer-related outpatient services excluding chemotherapy, (2) spending on cancer-related inpatient services, (3) utilization of select cancer-related outpatient services (evaluation and management, commonly used expensive billing codes, and radiation therapy sessions), and (4) the number of cancer-related hospitalizations. We used regression analyses to adjust for patient health risk factors and market characteristics. RESULTS: During the 6-month follow-up period, risk-adjusted spending on nonchemotherapy outpatient services was slightly lower among patients receiving chemotherapy in HOPDs than in POs ($12,183 [95% CI, $12,008-$12,358] v $12,444 [95% CI, $12,313-$12,5751; P <.05). Risk-adjusted cancer-related inpatient spending was higher in the HOPD group than in the PO group ($3996 [95% CI, $3837-$41561 vs $3168 [95% CI, $3067-$32681; P <.01). The HOPD group had fewer visits in all select outpatient services but had a higher number of hospitalizations than the PO group. CONCLUSIONS: Differences in cancer care spending by site of chemotherapy (HOPDs vs POs) vary by service type. Those differences are partially driven by utilization differences. As the site of chemotherapy shifts from POs to HOPDs, spending and utilization patterns in both settings need to be monitored.