Considering the biology of CRC, distant metastases might support the identification of high-risk patients for early recurrence and targeted therapy. Expression of a panel of druggable, metastasis-related biomarkers was immunohistochemically analyzed in 53 liver (LM) and 15 lung metastases (LuM) and correlated with survival. Differential expression between LM and LuM was observed for the growth factor receptors IGF1R (LuM 92.3% vs. LM 75.8%, = 0.013), EGFR (LuM 68% vs. LM 41.5%, = 0.004), the cell adhesion molecules CD44v6 (LuM 55.7% vs. LM 34.9%, = 0.019) and α2β1 (LuM 88.3% vs. LM 58.5%, = 0.001) and the check point molecule PD-L1 (LuM 6.1% vs. LM 3.3%, = 0.005). Contrary, expression of HGFR, Hsp90, Muc1, Her2/neu, ERα and PR was comparable in LuM and LM. In the LM cohort ( = 52), a high CD44v6 expression was identified as an independent factor of poor prognosis (PFS: HR 2.37, 95% CI 1.18-4.78, = 0.016). High co-expression of CD44v6/α2β1 (HR 4.14, 95% CI 1.65-10.38, = 0.002) and CD44v6/PD-L1 (HR 2.88, 95% CI 1.21-6.85, = 0.017) indicated early recurrence after hepatectomy, in a substantial number of patients (CD44v6/α2β1: 11 (21.15%) patients; CD44v6/PD-L1: 12 (23.1%) patients). Dual expression of druggable protein biomarkers may refine prognostic prediction and stratify high-risk patients for new therapeutic concepts, depending on the metastatic location.