Objective: The aim of this study was to evaluate the effectiveness and safety of low-dose interferon alpha-2a (IFNα2a) in Behçet’s syndrome (BS) patients with refractory vascular/cardiac or neurological involvement. Methods: In this retrospective cohort study, we consecutively included 25 BS patients with refractory vascular/cardiac (n = 16) or neurological involvement (n = 9) who received IFNα2a treatment in our center between June 2018 and September 2021. The low-dose IFNα2a (3 million IU, every other day) was used as an add-on treatment with the continuation of glucocorticoids (GCs) and immunosuppressants. Results: In total, 25 patients (20 males, 5 females) with a mean age of 31.92 ± 9.25 years were included. IFNα2a was administered for BS patients with refractory vascular/cardiac involvement (n = 16) and neurological involvement (n = 9). Before the initiation of IFNα2a, patients had insufficient response or intolerance to conventional therapies. After a median follow-up of 23 interquartile range (IQR), 11–30 months, all patients achieved clinical improvement. The Behçet’s disease Current Activity Form (BDCAF) score improved significantly (5 versus 0, median, p < 0.0001). BS Overall Damage Index (BODI) and vasculitis damage index (VDI) remain stable (p > 0.05). Decrease in erythrocyte sedimentation rate ESR; 24 (IQR, 12–43.5) versus 5 (IQR, 2.75–10.5) mm/h, p = 0.0001 and C-reactive protein CRP; 6.64 (IQR, 3.67–19.82) versus 1.24 (IQR, 0.24–3.12) mg/liter, p < 0.005 was achieved effectively. The median GCs dosage tapered from 26.25 (IQR, 11.88–41.25) to 10.00 (IQR, 7.50–10.63) mg/d, p < 0.0001. Immunosuppressants were also reduced in number (p < 0.005). No serious adverse events were observed during follow-up. Conclusion: Our study suggests that low-dose IFNα2a, combined with GCs and immunosuppressants, is well-tolerated and effective for BS patients with refractory vascular/cardiac or neurological involvement and has a steroid- and immunosuppressant-sparing effect.