Patients with lymphoma who have experienced a first relapse or progression and have disease deemed sensitive to salvage chemotherapy nevertheless have a high likelihood of having a second relapse. To decrease the likelihood of a second relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), interferon (IFN) α-2b was given in a prospective randomized international trial. Methods. In this trial, 221 patients with varying histologic diagnoses (8 small lymphocytic, 37 follicular, 9 mantle, 90 diffuse large B-cell, 20 peripheral T-cell, 3 high-grade B-cell non-Hodgkin lymphoma, and 54 Hodgkin lymphoma) were randomly assigned to receive no further treatment (arm A: 117 patients) or IFNα-2b, 3 MU three times weekly, for 18 months (arm B: 104 patients). Results. In arm B, 21 patients (20%) did not receive IFNα-2b because of early progression or absence of hematologic recovery, 29 patients (28%) completed the 18 months of treatment, and 54 patients (52%) interrupted treatment because of progression (23%) or toxicity (29%). Event-free survival and overall survival were not different between the two arms on an intent-to-treat analysis and also if analysis was restricted to patients who were alive and had not experienced disease progression three months after transplantation. The study was not sufficiently powered to evaluate effects in histologic subtypes. Conclusion. In this trial, post-autograft IFNα-2b did not improve outcomes in a heterogeneous group of patients with lymphoma.