Background: HF10 is a bioselected replication-competent oncolytic virus derived from HSV-1. Herein, we report the safety and efficacy data of HF10 + ipilimumab (ipi) combination treatment in a Phase II trial in melanoma. Methods: Key entry criteria: age ≥ 18 yrs, ECOG ≤ 2, Stage IIIB, IIIC, or IV unresectable melanoma, ipi naïve (IV administration) and measurable non-visceral lesion(s) suitable for injection. HF10 injected into single or multiple tumors (1 x 10⁷ TCID₅₀/mL/dose, up to 5mL depending on tumor size and number); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Dose limiting toxicity (DLT) defined as ≥ G3 non-hematologic/hematologic toxicity, ≥ G2 neurologic toxicity, or allergic event occurring within 1^st 3wks of therapy. Results: Of 46 pts enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with ≥ 1 prior cancer therapy for unresectable/metastatic melanoma. Most HF10-related AEs were ≤G2, similar to HF10 monotherapy. No DLTs were reported. 37% had ≥G3 AEs, the majority due to ipi. HF10-related ≥G3 AEs (n=3) were embolism, lymphedema, diarrhea, hypoglycemia, and groin pain. Of the 44 efficacy evaluable pts per irRC, BORR at 24 weeks was 41% (16% irCR and 25% irPR); disease stability rate was 68% (16% irCR, 25% irPR and 27% irSD). As of Feb 06, 2017, median PFS was 19 months and median overall survival was 21.8 months. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in pts with stage IIIB, IIIC, or IV unresectable or metastatic melanoma. Clinical trial information: NCT02272855