Pegylated-interferon plus ribavirin remains the most effective therapeutic regimen for patients with chronic hepatitis C. Thrombocytopenia is a common side effect of this treatment, often leading to discontinuation of a potentially curative therapy. We sought to determine the safety and efficacy of laparoscopic splenectomy in correcting the thrombocytopenia, thus allowing resumption of interferon therapy. Data was collected prospectively from September 2000 to November 2002 on all patients who underwent laparoscopic splenectomy for thrombocytopenia associated with interferon therapy and/or hepatitis C cirrhosis with portal hypertension. Demographic data, MELD score, platelet count, operative time, blood loss, spleen weight, complications, length of stay, and follow up time were calculated. Ten patients (7 male: 3 female) underwent laparoscopic splenectomy, with a mean age of 46 (range, 27-55), and mean BMI of 26 kg/m² (range, 21-32.4). All patients were Child's class A, with a mean MELD score of 9.1 (range, 6-11). A hand-assisted laparoscopic technique was used in 4 cases. Mean operative time was 193 min (range, 70-245), and blood loss averaged 146 ml (range, 10-600). Six patients received prophylactic platelet transfusions, and none required transfusion with packed red cells. Splenic weight averaged 1001 gm (range, 245-1650). Average length of stay was 2.7 days (range, 1-6). There were 4 patients with postoperative complications: self-limited atrial fibrillation (1), trocar-site cellulitis (1), and atelectasis (2). Follow up averaged 7.5 months. Postoperatively MELD score mean was 8.3 (range, 6-10). Platelet counts improved from a preoperative mean of 55,000/uL (range, 16K-88K) to 357,000/uL (range, 200K-492K) postoperatively and have remained above 100K during subsequent pegylated-interferon therapy. Currently, 2 patients have completed 36 weeks of pegylated-interferon with undetectable (<26 c/ml) viral counts 3 months post-treatment. Laparoscopic splenectomy is safe in the setting of portal hypertension and thrombocytopenia associated with chronic Hepatitis C infection. It can be performed with little blood loss, no need for red cell transfusion, and minimal perioperative morbidity. Laparoscopic splenectomy appears to effectively reverse thrombocytopenia and may allow these patients to safely resume interferon therapy.