Biomarkers for anti-angiogenic drugs in chemo-refractory metastatic colorectal cancer (mCRC) are lacking. We investigated the relationship between stanniocalcin 1 (STC1) and outcomes in patients treated with regorafenib in the TEXCAN and CORRECT trials. Baseline plasma STC1 protein levels were measured by ELISA from patients with chemo-refractory mCRC enrolled in TEXCAN (regorafenib n=48) and CORRECT (placebo n=211; regorafenib n=435). The relationship between STC1 levels and overall survival (OS) was assessed using a Cox proportional hazards model. The median STC1 value was increased in patients with chemo-refractory mCRC (1211 pg/mL) compared with previously untreated patients (215 pg/mL). Using an optimized cut-off, STC1 was prognostic for OS (HR 2.12, 95% CI 1.79, 2.50; P<0.001), with a median OS of 7.63 months in the STC1 low group (<1436.87 pg/mL; n=400) and 3.81 months in the STC1 high group (≥1436.87 pg/mL; n=246). The interaction p-value of LDH and treatment revealed no predictive effect of LDH levels on OS in terms of regorafenib (P=0.598). A predictive analysis suggested a significant association between STC1 and regorafenib for OS (interaction P=0.049). Median OS with regorafenib versus placebo was 8.32 versus 6.54 months in the STC1 low group (HR 0.83, 95% CI 0.66, 1.03; P=0.087) and 4.41 versus 3.09 months in the STC1 high group (HR 0.64, 95% CI 0.49, 0.84; P=0.001), respectively. Altogether, high STC1 protein levels have a predictive potential to characterize a population of patients with chemo-refractory mCRC and poor prognosis in whom regorafenib has an increased level of efficacy.