Background: Liver metastasis (LM) confers poor prognosis in metastatic colorectal cancer (mCRC). It has not been well understood whether tumor microenvironment (TM) varies throughout cancer treatment in the presence of LM. We therefore investigated the difference of TM between first-line (FL) and savage-line (SL) anti-angiogenic therapies and tested whether specific angiogenic cytokines could predict clinical outcome in mCRC patients. Methods: A combined cohort consisting of two cohorts (N = 125) was included in this study: 71 patients received first-line treatment with bevacizumab (FL cohort: median age, 60; median follow-up, 28.9 mos) and 54 patients received salvage-line regorafenib (SL cohort: median age, 65; median follow-up, 17.2 mos). Blood samples were obtained from all patients at baseline (BL) and during the treatment, and serum levels of nine angiogenic cytokines were measured using ELISA. Progression-free survival and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazard regression. Results: In univariate analysis for the combined cohort, right-sided CRC, primary unresected, KRAS wild-type, LM, metastatic site ≥2 and SL were associated with shorter OS, and LM and SL remained in multivariable analysis. Ang-2 and IL-8 levels at BL were significantly associated with LM and their cut-off values were 2190.3 pg/ml (CO_Ang2) and 15.1 pg/ml (CO_IL8), respectively, and no significant interaction was shown between cytokines and cohorts. Patients with Ang-2 levels ≥CO_Ang2 had shorter OS than those with Ang-2 levels < CO_Ang2 (HR2.57, 95%CI: 1.47–4.51, P = 0.001), while IL-8 levels ≥CO_IL8 was associated with shorter OS than < CO_IL8 (HR4.31, 95%CI: 2.11–8.79, P < 0.001). IL-8 levels ≥CO_IL8 remained as significant in multivariable analysis (HR 3.24, 95%CI: 1.47–7.16, P = 0.004). In change analysis, there was no significant correlation of variation of IL-8 and Ang-2 levels with clinical outcome after the first treatment cycle in both cohorts. Conclusions: Circulating IL-8 and Ang-2 levels reflect the TM in the presence of LM, of which IL-8 may serve as solid prognostic marker of anti-angiogenic therapy regardless of the timing of treatment for mCRC.