Background:Neuropsychiatric adverse effects of interferon (IFN) alpha are well known. There is little clinically relevant research on animal models of depression with recombinant human IFN alpha 2b (rhIFN-α2b).Aim:To identify an appropriate dose and duration of administration of recombinant human interferon alpha-2b (rhIFN-α2b) to establish a convenient and clinically relevant murine model of chronic rhIFN-α2b-induced depression using the forced swim test (FST).Materials and Methods:Using a 4×3 factorial design, rhIFN-α2b was administered subcutaneously to mice (n=180) in the dose range of 400, 800, and 1600 IU/g/day for 5, 10, and 15 days; saline-treated mice formed the control groups. In each group, 1 day after the last dose, the mice were assessed for immobility in the FST. In another experiment, at these same doses and time points, the effect of rhIFN-α2b on murine motility was assessed in the small open field.Results:We found that rhIFN-α2b significantly increased immobility in the FST. The immobility was detectable by day 5 and did not increase with duration of IFN treatment. The immobility was apparent with the 400 IU/g/day dose and was not greater at higher IFN doses. At no dose or time point did rhIFN-α2b alter murine motility in the small open field.Conclusion:We conclude that rhIFN-α2b-induced behavioral despair, represented by immobility in the FST, is not due to reduced basal motility. The FST may therefore be used as a convenient Swiss albino mouse model of chronic rhIFN-α2b-induced depression with a 400–1600 IU/g/day dose administered subcutaneously for 5–15 days. The most economical model is 400 IU/g/day administered for 5 days