Background and Aims: Chronic hepatitis C (CHC) viral infection has a major impact on our health care system. The emergence of direct-acting antiviral agents (DAA) has made treatment simple (oral), efficacious, and safe. However, treatment is expensive and access is variable. Despite great treatment outcomes, only a minority of patients with CHC receive antiviral therapy. This study identifies the barriers to treatment in CHC infection. Methods: Study recruited all hepatitis C antibody-positive patients between 2012 and 2016 from a large academic teaching hospital in New York City. Demographic information, clinical data, and insurance information were reviewed. Statistical analysis performed with OR and p < 0.05 reported. Result: A total of 1,548 patients with hepatitis C antibody-positive titer were included in the initial analysis. One thousand and twenty-four patients were forwarded to the final analysis after exclusion of 524 patients (for distant resolved hepatitis C viral [HCV] infection [n = 42], patients cured with interferon-based regimens [n = 94], patients with comorbid conditions [n = 176], and patients with an incomplete medical chart [n = 212]). In the intention to treat cohort of 1,024 patients, 204 patients achieved a sustained virological response after receiving DAAs (n = 204/1,024 – 20%). The majority of patients had not received DAAs (n = 816/1,024 patients – 80%). Multiple factors resulted in hepatitis C viral infection (HCV) patients not receiving DAAs including the following primary factors: (a) lost to follow-up clinic visits and poor adherence to clinic appointments (n = 548 [67%]; p value <0.0001), (b) active substance abuse (alcoholism and IV drug abuse; n = 165 [20%]; p value 0.22), (c) patients with significant psychiatric illness (n = 103 [12.7%]; p value 0.015), and subgroup analysis revealed that 188 (188/1,024 – 12%) patients had human immunodeficiency virus-1 (HIV-1) and HCV coinfection. Majority of HCV/HIV coinfected patients had not received DAAs (n = 176 [97%]; p value <0.0001, OR 4.46). The etiology of nontreatment in coinfected HIV/HCV patients was 73.3% poor adherence, 11.5% active substance abuse including alcohol and IV drug use, and 9% significant psychiatric illness and 6.2% multiple reasons for not receiving HCV treatment. Conclusion: Multifactorial barriers are preventing hepatitis C patients from receiving effective DAA therapy. Primary factors include poor compliance, substance abuse, and significant psychiatric illness, with significant overlap between these groups. Subgroup analysis showed a substantial number of high-risk patients with HIV/HCV coinfection did not receive DAA therapy. A multidisciplinary clinic approach with a hepatologist, ID physicians, social worker, and behavioral health psychologist and case manager should provide a solution to improve diagnosis and treatment with DAA.