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Background Talimogene laherparepvec (T-VEC) is an oncolytic herpes simplex virus therapy approved for treatment of unresectable and metastatic melanoma. However, real-world use often occurs in heavily pretreated patients, where evidence of effectiveness remains limited. This study evaluates treatment responses and clinical factors influencing T-VEC outcomes in patients with diverse treatment histories.Methods We analyzed patients with metastatic melanoma treated with T-VEC between 2015 and 2024. Objective responses (OR), complete response (CR) and partial response were assessed using univariate and multivariate Cox regression models. Durability of responses, progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan-Meier estimates.Results Among 121 patients, 105 (87%) patients received ≥1 prior lines of systemic therapy; 48 (40%) had a current or prior history of distant metastatic disease, and 42 (35%) had both injectable and non-injectable disease at the T-VEC initiation. Median PFS was 12.2 months (95% CI 6.2 to 20.9), and median OS was 35.5 months (95% CI 25.8 to 63.9). Of 113 evaluable patients, 76 (67%, 95% CI 58% to 76%) achieved an OR, including 39 (35%, 95% CI 26% to 44%) CR. The probability OR by 6 months was 56% (95% CI 46% to 65%). Of the 39 patients achieving CR, 37 (95%) remained alive and progression-free at last follow-up (median 19.1 months). In multivariate analysis, the adjusted HR (aHR) for OR in patients with non-injectable distant metastases at T-VEC initiation relative to those without was 0.43 (95% CI 0.23 to 0.78; p=0.006). The aHR for OR among those immunosuppressed compared with those not immunosuppressed was 0.18 (95% CI 0.04 to 0.69; p=0.013), indicating a reduced likelihood of response for patients who were immunosuppressed. Unadjusted HRs for achieving an OR after 1, 2, and ≥3 prior therapies (vs none) were 1.20 (95% CI 0.57 to 2.52; p=0.627), 1.21 (95% CI 0.52 to 2.80; p=0.653), and 0.77 (95% CI 0.35 to 1.68; p=0.507), respectively.Conclusions This study demonstrates T-VEC’s potential efficacy in achieving meaningful disease control and response durability in patients with unresectable and/or metastatic melanoma, including those with diverse prior-treatment histories and comorbidities.