Translocation t(11;18) is a factor predictive of poor response to treatment of gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). We treated 13 patients with t(11;18)-positive gastric MALT lymphoma with the combination of rituximab and chlorambucil (nine patients as first treatment and four as second line therapy). The response to treatment was assessed on endoscopy, histology and molecular parameters including clonality and t(11;18) (median follow-up: 2 years). Macroscopic lesions disappeared in all cases. Histological remission was observed in 100% of the patients at the end of follow-up. At week 25, B cell monoclonality and t(11;18)-positive tumor cells were still detected in 77% and 73%, respectively. However, at long term follow-up, the tumor B cell clone was present in only 30% whereas the t(11;18) was still detected in 70%. The combination of rituximab - chlorambucil is highly effective in t(11;18)-positive gastric MALT lymphoma. Molecular disease persists despite histological remission. t(11;18) is more sensitive than B cell clonality for the monitoring of residual molecular disease.