Background: Progression of disease within two years from start of therapy (POD24) is linked with poor outcome in follicular lymphoma. It is less clear whether POD24 affects overall survival (OS) also in extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). Methods: We analyzed the dataset of the IELSG19 clinical trial (training set) to determine whether POD24 is associated with inferior OS. The study population included 401 EMZL patients (131 randomly assigned to chlorambucil treatment, 138 to rituximab and 132 to chlorambucil plus rituximab). Reproducibility was analyzed in an independent cohort (validation set) of 218 patients who received systemic treatment (chemotherapy, immunotherapy or both). In both, training and validation sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without progression. Overall survival (OS) was calculated from disease progression in patients with POD24 and from 24 months after start of treatment in those without POD24 (reference group). Results: POD24 was observed in 69 of 401 patients of the IELSG19 study and 58 of 218 patients in the validation cohort. In the training set, the 10-year OS rates were 64% in the POD24 group and 85% in the reference group (HR = 2.42, 95%CI, 1.35-4.34; log-rank P = 0.002) and POD24 predicted poor outcome regardless of treatment type (multivariable Cox model, P = 0.003). The prognostic impact of POD24 was confirmed in the validation set, with 10-year OS rates of 48% in the POD24 group and 71% in the reference group (HR = 2.17, 95%CI, 1.20-3.93; log-rank P = 0.009). Conclusions: In patients with EMZL who received front-line systemic treatment, POD24 is associated with poorer survival and may represent a useful endpoint in future prospective clinical trial.