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Simple Summary: We investigated the ability of using protein adipophilin (ADP) levels to predict long-term survival after liver surgery in patients with colorectal liver metastases (CRLMs). We studied 102 patients with CRLM who had liver surgery between 2006 and 2022. ADP levels were examined in the surgically removed tumors. Long-term outcomes for ADP-positive (n = 51) and ADP-negative (n = 51) groups were compared. Rates of survival without disease recurrence and overall survival were significantly decreased for ADP-positive patients relative to ADP-negative patients. Analyses demonstrated that patients with ADP-positive CRLM had a worse prognosis than those with ADP-negative CRLM, as reflected by both survival without disease recurrence (p = 0.002) and overall survival (p = 0.003). Thus, the ADP level was able to predict the survival of patients with CRLM after liver surgery. Background/Objectives: Adipophilin (ADP) is a protein associated with lipid droplets, and its expression is related to poor prognosis in certain cancers. However, its impact on the survival of patients with colorectal liver metastases (CRLMs) remains unclear. This study investigated the impact of ADP expression on long-term survival following hepatectomy in patients with CRLM. Methods: We retrospectively analyzed 102 consecutive patients who underwent hepatectomy between 2006 and 2022. ADP expression was examined in resected specimens through immunohistochemical staining using tissue microarrays. Long-term outcomes for ADP-positive (n = 51) and ADP-negative (n = 51) groups were compared with Kaplan–Meier survival analysis. Results: We found significantly decreased 5-year recurrence-free survival (RFS) and overall survival (OS) rates for ADP-positive patients relative to ADP-negative patients (29.4% versus 52.1%, respectively; p = 0.001 and 43.7% versus 72.2%, respectively; p = 0.003). Moreover, multivariate Cox hazards analysis demonstrated that patients with ADP-positive CRLM had a worse prognosis after hepatectomy than those with ADP-negative CRLM, as reflected by both RFS (HR 2.46, 95% CI 1.39–4.36, p = 0.002) and OS (HR: 2.89, 95% CI 1.43–5.85, p = 0.003). Conclusions: ADP expression had a significant prognostic impact on the survival of patients with CRLM following liver resection and may aid in optimal treatment planning. [ABSTRACT FROM AUTHOR]