Background: Axitinib has demonstrated high efficacy with well-controlled adverse events (AEs) for advanced renal cell carcinoma (RCC). Recently, nivolumab has been approved for advanced RCC. However, it is very expensive in Japan and may cause severe immune-related AEs. There is no clue to choose axitinib or nivolumab as the second-line for advanced RCC. Previously we identified the gene set which may predict poor prognosis of RCC patients (Takahashi m et.al., Proc Natl Acad Sci U S A., 98: 9754, 2001) and have sought to elucidate whether insulin receptor (INSR) expression in the gene set may predict the resistance for axitinib as a biomarker. Methods: Axitinib was administered in 36 patients in our department between January 2008 and April 2015. Median age was 70 (36-84) years old with 22 males and 14 females. Histological subtype included clear cell RCC (n=27, 75.0%), clear cell + sarcomatoid component (n=3), collecting duct carcinoma (n=2), papillary, sarcomatoid, mucinous tubular and spindle cell carcinoma (MTSCC), and unknown in each one. Axitinib was administered in two patients as the first line, 21 patients as the second line, and 13 patients as ≥ the third line. Tissue of primary tumor was available in 20/36 patients, including 16 clear cell RCC and 4 other subtypes. Immunohistochemical INSR expression was examined and correlated with survival of the patients with axitinib. Results: Objective response rate was 27.6%, progression-free survival (PFS) was 16.3 months, and overall survival (OS) was 41.9 months in clear cell RCC patients. Patients with low INSR expression (n=7) had significantly shorter PFS (68 vs. 586 days, p<0.001) and OS (169 vs. 1027 days, p=0.004) compared with those with high INSR expression (n=13). If only clear cell RCC was evaluated, patients with low INSR expression (n=3) had significantly shorter PFS (77 vs. 586 days, p=0.008) and OS (294 vs. 1027 days, p=0.016) compared with those with high INSR expression (n=13). Conclusions: Axitinib was highly effective for advanced clear cell RCC. However, immunohistochemically low expression of INSR in the primary tumor may predict the resistance for axitinib and those patients may be more suitable for immune checkpoint inhibitors.