Maintenance interferon alpha (IFN-α) immunotherapy after induction chemotherapy prolongs progression-free survival (PFS) in untreated follicular lymphoma (FL). Little information is available about IFN-α use in relapsed FL. This study aims to evaluate the benefit of IFN-α as a treatment of low-burden FL relapse. This single-centre retrospective study identified 20 patients treated in 27 cases with IFN-α. We analysed all cases of IFN-α treatment in patients with low-burden FL in clinical relapse (11), partial response (5) or only with molecular minimal residual disease (MRD; 5). The treatment schedule was 3MIU IFN-α three times a week alone (16) or combined with four weekly rituximab (R; 11), according to the institution's policy. Except for the molecular relapses, responses were evaluated according to the IWG 1999 criteria. MRD was defined as a repeatedly detectable BCL2-IgH rearrangement in peripheral blood or bone marrow. In 22 cases of clinical relapses or partial responders, overall response rate was 68 %, with 55 % complete responses. Median PFS was 20.9 months (95 % confidence interval (95 % CI), 0-64.9) with 20.9 and 48.7 months in the IFN and R-IFN groups, respectively (p = 0.4). The median PFS of the five MRD cases was 133 months (95 % CI, 103-165). The Follicular Lymphoma International Prognostic Index score calculated at initiation of IFN-α treatment was predictive of time to relapse (p = 0.036). These results compare favourably with previous reports of the efficacy of R alone, and of R with IFN-α in relapse. Further research is required to explore the role of IFN-α in the management of FL.