Background and Aim The introduction of sofosbuvir has revolutionized the treatment of chronic hepatitis C. This study was planned to observe whether the efficacy and tolerability of sofosbuvir-based regimens demonstrated in phase 3 clinical trial results translate into real-life clinical practice. Methods This prospective, non-randomized observational study conducted in Dayanand Medical College and Hospital, Punjab, included all consecutive treatment-naive patients with chronic hepatitis C (genotypes 1-5) who were treated with sofosbuvir-based regimens. Response to therapy was assessed at week 4 (rapid virological response), week 12 or 24 (end of treatment response), and 12weeks after cessation of therapy (sustained virological response [SVR]). Results Of 947 patients diagnosed with chronic hepatitis C virus and considered for treatment with direct-acting antivirals, 736 patients (77.1%) opted for treatment (age 45.110.1years, 64% men, genotype 3 [80%], genotype 1 [14.7%], and genotype 4 [4.9%]). Viral load was high (>600000IU/mL) in 361/736 (49%); 330 patients (44.8%) had cirrhosis (80 [14.3%] were decompensated). Patients with genotypes 1, 4, and 5 (n=135) were treated with triple drug regime (pegylated interferon, ribavirin, and sofosbuvir) for 12weeks. Patients with genotype 3 (n=589) were treated either with dual therapy (sofosbuvir and ribavirin) for 24weeks (n=405) or triple therapy for 12weeks (n=184). SVR was achieved in 453/473 (95.8%). SVR rates did not differ among different genotypes but were higher in non-cirrhotics. Conclusion Sofosbuvir-based treatment regimens achieve high SVR rates in real-life cohort of Indian patients with chronic hepatitis C infection (including those with cirrhosis).