Background: Data on outcomes of direct-acting antiviral agents(DAAs) in hepatitis C virus (HCV)-related extrahepatic manifestations (EHMs) is scarce. We aimed to assess the safety and efficacy of sofosbuvir (SOF)-based regimens in HCV- related EHMs. Methods: 100 patients with HCV-related EHMs were recruited from three tertiary care centers in Egypt. SOF-based regimens included 35 patients who received SOF-based DAAs combination for 3 months, 23 patients who received SOF plus ribavirin (RBV) for 6 months, and 42 patients who received pegylated-interferon (INF)/RBV plus SOF for 3 months. The virological response was assessed by the sustained virological response (SVR12), clinical response (CR) included resolution of symptoms and signs of EHMs, and the immunological response was assessed by the disappearance of cryoglobulins at end of treatment and SVR12. Results: Overallend of treatment virological,complete CR, and immunological responses were 96%, 95%, and 92 % respectively, while SVR12, CR, and immunological responses were 92%, 89%, and 69.2% among regimens. CR was higher in DAAs combinations without RBV (97.1%), less for IFN-based regimen (85.7%), and the least with SOF+ RBV (82.6%). Recurrence and adverse events were higher in SOF+RBV. Conclusion: Successful HCV eradication by DAAs was associated with clinical and immunological improvement of EHMs.DAAs combination regimen was safer and more effective in achieving SVR and CR.