Background: Hypersplenism due to chemotherapy-related liver injury has been associated with severe thrombocytopenia that may preclude continuation of systemic therapy for cancer patients. Patients treated for metastatic colorectal cancer (mCRC) are among the most common patients affected by hypersplenism. Cessation of systemic therapy invariably leads to progression of disease. While partial splenic embolization has been employed successfully to reverse the effects of hypersplenism, the role of laparoscopic splenectomy for this problem has not been completely defined. Methods: A retrospective review was conducted of mCRC patients treated with laparoscopic splenectomy at our institution to reverse severe thrombocytopenia due to chemotherapy-related hypersplenism. An endpoint assessed was the ability to resume therapy after splenectomy. Results: Six patients with mCRC and hypersplenism requiring cessation of systemic therapy underwent laparoscopic splenectomy. All (6) patients had a postsurgical platelet count >150 × 103/µl and resumed chemotherapy after surgery. Median platelet count prior to surgery was 66 × 103/µl, and just prior to resuming systemic therapy it was 399.5 × 103/µl. Median spleen size was 14.0 cm. There were no surgical complications. Mean hospital stay was 2.8 days and the median time from surgery to resumption of therapy was 23.5 days. Conclusions: Laparoscopic splenectomy appears to offer selected patients with mCRC the opportunity to resume systemic therapy that otherwise would be discontinued due to thrombocytopenia from hypersplenism.