Purpose The interaction between interferon treatment and BRAF mutation status among melanoma patients have yet to be evaluated. The present study aims to assess the intermediate dose interferon (IDI) in stage III melanoma patients with respect to BRAF mutation status. Methods A total of 46 adult lymph node-positive primary skin melanoma patients (23 BRAF-mutant and 23 BRAF-wild) with available information on the mutational status of the oncogene BRAF V600E were included in the analysis. BRAF V600E mutation was detected using the real-time PCR in the formalin-fixed paraffin-embedded samples. All the patients were treated with adjuvant IDI. IFN-alpha-2b was administered 10 MU per day, subcutaneously, three times per week for 1 year. Results The distribution of patient numbers between the clinicopathological variables and BRAF mutation status was well balanced. Most of the patients relapsed (83%); however, no significant differences were found between recurrence frequencies and recurrence sites in accordance with BRAF mutation status. BRAF-mutant melanomas were found to be significantly advantageous in disease-free survival (HR 0.464, p = 0.03). More deaths occurred in BRAF-wild-type patients (67%) (p = 0.03), and BRAF mutation was found to be a favorable prognostic factor for overall survival (HR 0.373, p = 0.04). Conclusion The presence of BRAF mutation in stage III melanoma patients treated with IDI might contribute a favorable effect on both disease-free survival and overall survival.