Chemotherapy remains the main choice of treatment for the management of unresectable or metastatic colorectal cancer. However, drug resistance is a major problem, limiting the effectiveness of the chemotherapies presently used to treat cancer. During treatment, drug resistance can also be acquired by tumors that are initially sensitive to chemotherapy. We present a case of metachronous splenic recurrence after a curative resection of appendical cancer with ovarian metastasis, although the patient had been treated with 5-FU/LV followed by mFOLFOX6 after surgery. Molecular analyses by RT-PCR also showed that the residual tumor after chemotherapy has cancer cells overexpressing 5-FU/l-OHP based chemotherapy-resistant genes. Therefore, it was suggested that a careful assessment of the disease status be undertaken during chemotherapy to ensure that the possibility of surgical resection, especially of the re-growth or partial response tumors, was not missed, since several genes, chemoresistant to the agents used, can be induced in residual tumors during chemotherapy.