OBJECTIVES: An earlier analysis in first-line treatment of RCC patients with similar baseline characteristics demonstrated significantly greater costs with sunitinib than sorafenib. Evidence from case series supports the use of sorafenib or sunitinib sequential therapy for RCC disease control. Direct medical costs associated with each sequence were quantified.  METHODS: Patients in MarketScan®, a U.S. health care claims database covering all U.S. census regions and >18 million lives annually from 2002-2009, were retrospectively analyzed. Inclusion: ≥2 RCC claims (ICD9 189.0; 198.0), continuous healthcare coverage, ≥1 switch (sorafenib to sunitinib; sunitinib to sorafenib), >180 days’ coverage before switch date. Observation period: first-line therapy ≤12 months before switch, ending ≤12 months after switch. Second-line therapy (switch) ended with next dispensing of sorafenib, sunitinib, bevacizumab, or temsirolimus; disenrollment; death; or study end (March 31, 2009). A person-time approach was used. Limitations include physician coding and lack of disease staging. RESULTS: At time of switch, no significant differences in baseline characteristics existed between groups (sunitinib, n=153; sorafenib, n=119), except longer enrolment in health plan in patients who received sorafenib first (12.4 vs 8.8 months; P<0.0001) and higher prevalence of anemia in patients who received sunitinib first (52.9% vs 32.8%, P<0.001). Univariate incremental total per member per month (PMPM) medical costs in those who received sunitinib first were $1639 (P =0.0003) more than those treated with sorafenib first, largely due to significantly higher outpatient costs PMPM in those who received sunitinib first ($1252; P<0.0001). Overall, this represents an annual cost savings of $19,668 in RCC patients initially treated with sorafenib.   CONCLUSIONS: In this retrospective US claims database analysis, we observed statistically significantly lower costs in RCC patients initially treated with sorafenib, the difference mainly attributable to outpatient costs. Future cost analyses should be incorporated into prospective trials of RCC sequencing.