Background: BRAF/NRAS mutations are predictors of poor prognosis in melanoma. High-dose interferon (HDI) is the only drug approved by FDA as adjuvant therapy in high risk resected melanomas. However, efficacy of HDI in high-risk melanomas harboring BRAF/NRAS mutations has not been evaluated systemically. This study aimed to clarify whether there is beneficial effect of HDI in these patients. Methods: Melanoma patients, after melanoma resection, with BRAF mutation (Exon 15) or NRAS mutation (Exon 2) in melanoma of high risk (Stage IIB to Stage IIIC) were enrolled in this study. Patients were randomized (ratio of 2:1) into 1-year adjuvant HDI therapy group (n = 88) and observation group (n = 52). The endpoint was disease-free survival (DFS). The median follow-up is 16 months till Dec. 2014. Somatic mutations were detected by DNA sequencing. All the statistical analyses were performed using SPSS 16.0 software. Results: The proportion of stage IIB/IIC and III disease were 55.0% and 45.0%, respectively. 53.6% patients were acral melanomas. Primary ulceration was found in 52.9% lesions. Of the 140 patients, 108 cases harbored BRAF mutation, and 32 cases with NRAS mutations. At the end of follow-up, 55% patients had metastatic or local recurrence. The overall median DFS was 19.0 months. DFS in HDI group was significantly longer than observation group (21.0 months vs. 10.0 months, p = 0.002). DFS of HDI vs. observation group were 19.0 vs. 9.0 months (p = 0.021) in BRAF-mutated patients. But stratified analysis did not show significantly DFS improvement of HDI in acral or stage IIB/IIC subgroups in BRAF-mutated patients. NRAS-mutated patients did not get significantly benefit from HDI therapy (DFS: 24.0 months vs. 20.0 months, p = 0.21). Stratified analysis did not show significantly different in DFS between two groups either in different stages (stage IIB/IIC vs. III) or in different subtypes (Non-CSD/CSD vs. acral). Conclusions: In the BRAF-mutated high-risk melanoma, HDI may provide beneficial effect in the resected patients. However, more powerful adjuvant therapy should be explored for NRAS-mutated melanoma patients.