Oxaliplatin-based chemotherapy regimens are currently a standard of care for the treatment of colorectal cancer (CRC) in both the adjuvant treatment and metastatic disease settings. Significant improvements in outcomes have been achieved with oxaliplatin-based combinations in these settings when compared with administration of 5-fluorouracil alone. Pathologic evaluation of normal liver from patients undergoing neoadjuvant oxaliplatin treatment has identified histologic evidence of sinusoidal injury, although the effect of this finding on patient outcomes after hepatic resection appears to be minimal. This article describes the use of oxaliplatin-based chemotherapy in 6 patients with stage III or IV CRC who developed evidence of noncirrhotic portal hypertension. These patients developed complications of portal hypertension including esophageal or hemorrhoidal varices with bleeding, splenomegaly with associated thrombocytopenia, and ascites. In each case, oxaliplatin-induced hepatic sinusoidal injury was identified as the most likely factor contributing to the development of noncirrhotic portal hypertension. The literature on hepatic sinusoidal injury after oxaliplatin is reviewed and the proposed pathophysiology is discussed.