Hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, including neurological complications. However, its impact on the outcome of carpal tunnel release surgery remains poorly understood. This study aimed to investigate whether HCV infection affects the prognosis of carpal tunnel surgery. Methods: This prospective comparative study enrolled 24 patients with carpal tunnel syndrome divided into two groups: 12 patients with untreated HCV infection and 12 patients without HCV infection. All patients underwent open carpal tunnel release surgery with follow-up evaluations at 2 weeks, 3 months, and 6 months post-surgery. Outcomes assessed included relief of tingling, pain severity (Visual Analogue Scale), nerve conduction studies, and wound healing. Results: Both groups had comparable demographic characteristics and preoperative clinical findings. Post-operatively, significant differences emerged: persistent tingling at 6 months was observed in 75% of HCV patients versus 8.3% of non-HCV patients (p<0.001). Pain severity remained significantly higher in the HCV group throughout follow-up, with 50% reporting moderate to severe pain at 6 months compared to complete resolution in the non-HCV group (p<0.001). Delayed wound healing occurred in 75% of HCV patients versus 16.7% of non-HCV patients (p=0.004). Nerve conduction studies showed better improvement in the non-HCV group. Conclusions: HCV infection significantly impacts the prognosis of carpal tunnel surgery, being associated with persistent symptoms, delayed wound healing, and poorer nerve recovery. These findings suggest that HCV status should be considered when planning carpal tunnel release.