We have earlier shown an advantage in overall survival for malignant lymphoma (ML) patients who received combined Interleukin-2 (rIL-2) and interferon alpha (IFN-alpha) immunotherapy after autologous stem cell transplantation (AutoSCT) in comparison with historic controls. On the basis of these results, we initiated a control prospective randomized multicenter 2-arm study, comparing the same combined immunotherapy treatment versus control for patients with malignant lymphoma after AutoSCT. One hundred nine patients were included in this study. After AutoSCT, patients were randomized either to the treatment group or to the control group. Patients in the treatment group received daily subcutaneous injections of rIL-2 6x10 IU/m/d for 5 consecutive days followed by 2-weeks rest period. Subsequently, they were treated daily with rIL-2 6x10 IU/m/d combined with INF-alpha 3x10 U/d for 5 consecutive days per week for 4 consecutive weeks. After 4 weeks of rest, IFN-alpha 3x10 U was administered for the next 6 months 3 times per week. Patients in the control group were followed up at the outpatient clinic. There was a significant enhancement of survival (P=0.05) and a clear trend in disease-free survival in favor of NHL patients receiving post-AutoSCT immunotherapy, in comparison with the control group. Eighty-nine percent of patients with NHL treated with immunotherapy were alive and 64% were disease free. In the control group, 66% of patients survived and 46% were disease free. Among the HL patients no significant differences were observed regarding survival, disease-free survival, and relapse rate. No serious toxicity events were observed. These results suggest that outpatient administered immunotherapy with IFN-alpha and rIL-2 is relatively well tolerated and may intensify remission in NHL patients, but not HL patients after AutoSCT.