PURPOSE: Cancer care has increasingly shifted from physician offices (MDOs) to hospital-based outpatient departments (HOPDs). This study compared the proportion of patients receiving optimal, evidence-based anticancer drug regimens and the cost of care when administered in these sites. METHODS: Patients with breast, lung, or colorectal cancer were identified from a large health insurance database. Anticancer drug regimens were considered on pathway when they were on the payer’s program list of optimal regimens when administered. Anticancer drug–related costs included all patient- and plan-paid costs on claims for anticancer drugs over the 6-month postindex period; total per-patient costs were summed over all claims in that period. RESULTS: A total of 38,140 patients (MDO, n = 18,998; HOPD, n = 19,142) were included. On-pathway status was similar in HOPDs (59.5%; 95% CI, 58.6% to 60.4%) versus MDOs (60.8%; 95% CI, 59.8% to 61.8%; P = .069). HOPDs had substantially higher costs. Adjusted cancer drug–related costs were $63,763 (95% CI, $62,301 to $65,224) for HOPDs versus $36,500 (95% CI, $35,729 to $37,271) for MDOs ( P < .001); adjusted total costs were $115,843 (95% CI, $113,642 to $118,044) for HOPDs versus $77,346 (95% CI, $76,072 to $78,620) for MDOs ( P < .001). For Medicare Advantage, adjusted total costs were $61,812 for HOPDs compared with $62,769 for MDOs; adjusted drug-related costs were $31,610 for HOPDs compared with $33,168 for MDOs. For commercial insurance, total costs were $119,288 for HOPDs compared with $77,613 for MDOs; drug-related costs were $65,930 for HOPDs compared with $36,366 for MDOs. CONCLUSION: Total and cancer drug–related per-patient costs were higher in HOPDs versus MDOs, but on-pathway status was similar. The cost differential between HOPDs and MDOs was driven by commercially insured members rather than Medicare Advantage members.