BACKGROUND: We report the histopathological results of a novel "inversed" strategy designed to manage patients with colorectal cancer (CRC) who have synchronous liver metastases by using chemotherapy first, liver surgery second, and resection of the primary tumor as a final step. This study was designed to compare the response to chemotherapy in liver metastases, primary tumors, and locoregional lymph nodes. METHODS: Twenty-nine patients with stage IV CRC received a combination of oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin (OCFL) for 3-4 months. Histological response to chemotherapy was assessed by using a tumor regression grading (TRG) score based on presence of residual tumor cells and extent of fibrosis. RESULTS: Median age of patients was 56 (range, 37-69) years. Primary tumor location was right colon (n = 5), left colon (n = 7), and rectum (n = 17 patients). TRG scores correlated across disease sites (Spearman correlation coefficients for TRG in the primary tumor and lymph nodes was 0.59 [P = 0.005]; for the primary tumor and metastases 0.44 [P = 0.021]; and for lymph nodes and metastases 0.58 [P = 0.006]). Complete absence or poor tumor response (TRG4/5) was significantly more frequent in primary tumors (35.7%) and locoregional lymph nodes (38%) than in liver metastases (6.9%; McNemar test, P = 0.02). Two patients had a complete pathologic response (pT0N0M0). CONCLUSIONS: In patients with stage IV colorectal cancer, liver metastases exhibit a better histological response than primary tumors to OCFL neoadjuvant chemotherapy.