Background: Randomized clinical trials showed improved overall survival (OS) of advanced gastroesophageal adenocarcinoma (GEA) patients treated with second-line taxane or irinotecan. However, most data on irinotecan efficacy in this setting come from large Asian trials. We retrospectively analyzed clinical effectiveness and toxicity of irinotecan in a cohort of patients with advanced GEA treated in our department. Methods: Advanced GEA patients who received at least one cycle of second-line irinotecan were eligible for inclusion. Irinotecan was administered every 3 weeks at an initial dose of 250mg/m(2) of body surface area with subsequent gradual (every 50 mg/m(2)) dose escalation up to 350 mg/m(2), in the case of good treatment tolerance. OS was estimated using the Kaplan-Meier method. A multivariate Cox regression analysis was used to examine the association between clinical and laboratory parameters and survival. Results: A total of 48 patients were identified. Median OS was 6.2 months [95% confidence interval (Cl): 3.9-7.6]. In multivariate analysis, age < 65 years, baseline total lymphocyte count (TLC) < 1500/mu l and presence of peritoneal metastases were associated with shorter OS. Most adverse events were grade 1-2 and included: anemia (52.3%), leukocytopenia (40.9%), neutropenia (59.1%), nausea (25.0%), vomiting (31.8%), diarrhea (31.8%), anorexia (29.5%) and fatigue (43.2%). Febrile neutropenia occurred in three patients (6.8%). Nine patients (20.5%) experienced a toxicity grade 3-4 of any kind. Conclusions: This retrospective analysis confirms clinical effectiveness and manageable toxicity of second-line irinotecan in an unselected cohort of advanced GEA patients. Age < 65years, baseline TLC < 1500/mu l and presence of peritoneal metastases were independent prognostic factors associated with shorter OS.