Background: A compromised immune-surveillance plays an important role in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). Talimogene laherparepvec (TVEC) is an HSV-1 oncolytic immunological agent FDA approved for the local treatment of unresectable recurrent melanoma. It is proposed that T-VEC directly destroys cancer cells, and induces production of GM-CSF to enhance systemic antitumor immune recognition. This proposed mechanism of action supports the innovative approach to implement TVEC in the management of cSCC. Methods: Immunocompetent patients > 18 years of age and diagnosed with at least one > 0.5 cm to < 5.0 cm, primary and histologically confirmed well-moderate differentiated cSCC, without evidence of perineural or vascular invasion were eligible to participate. Unresectable lesions or patients unable/unwilling to undergo standard of care treatment were eligible to participate. Study lesions include target injected lesions (TILs) and target non-injected lesions (TNILs). A total of up to 5 TILs were selected per subject. If feasible, target non-injected lesions (TNILs) were also selected in eligible participants to evaluate for abscopal effect. Every TIL was injected up to 4 times based lesion diameter according to current TVEC approved protocol administration and followed for 1yr after the 1^st injection. The primary endpoint of the study was to evaluate the overall response rate (ORR), defined as the proportion of subjects who achieved complete response (CR) and partial response (PR) in the TILs. Safety and adverse effect profile (AEs), duration of ORR, time to response (TTR), durable response rate, and time to progression, were the secondary endpoints included. A Simon 2 stage design was used. Total sample size was calculated to be 20 subjects. Seven subjects were recruited for stage 1 with a plan to recruit an additional 13 patients if five or more subjects met the primary endpoint in stage 1. Results: The interim analysis was conducted after the 7th participant completed Visit 8 (352-266 days from study initiation). For the primary endpoint, all 7 participants achieved an overall complete response (100%; 95% CI: 59.0-100%). NCI CTCAE (v. 4.0) was used to assess the safety and adverse effect profile. All AEs ranged from grades 1-2, and most commonly experienced transient fatigue (n = 3/7), flu like symptoms (n = 2/7) and headaches (n = 2/7). The mean time to response was 43.4 (SD 31.6) days and for duration of ORR 190.0 days (SD 39.3) at the time of analysis. The 2 TNILs evaluated in the interim analysis also demonstrated 100% CR (95% CI: 15.8-100%). Conclusions: TVEC showed extremely impressive ORR for patients with cSCC with a 100% CR in stage 1 of our pilot study. AE profile of TVEC was mild and was well tolerated. Completion of the study will further assess this high response rate. Clinical trial information: 03714828.