For many years the only available therapy for chronic hepatitis C virus (HCV) infection was interferon-based therapy. Interferons are a family of cytokines that are an essential part of the body’s natural response to viral pathogens. In 1991, interferon-α (IFN-α) injections were first approved by the Food and Drug Administration for the treatment of HCV infection and remained the backbone of therapy until late 2014. As monotherapy, IFN-α injected thrice weekly yielded low sustained virologic response (SVR) rates. In 1998, the addition of ribavirin, a broad-spectrum, non-specific antiviral agent, decreased liver inflammation alone and, in combination with IFN-α, increased the SVR rate; however, the addition of ribavirin also increased side effects. In the early 2000s, IFN-α plus ribavirin combination treatment was further improved by the development of longer-acting pegylated IFN-α (PegIFN-α). While this reduced the need for subcutaneous injections from three times a week to once a week which improved patients’ adherence, the increase in SVR with PegIFN-α over standard IFN-α was relatively modest. Further, drug-related side effects remained problematic, limiting HCV treatment uptake and effectiveness. In the early direct-acting antiviral (DAA) era, PegIFN-α and ribavirin were used in combination with DAAs to prevent drug resistance and increase the SVR rate. With the advent of combination DAA regimens, the role of IFN-α decreased dramatically and, in late 2017, IFN-α was no longer recommended by professional societies as a first-line treatment for any HCV genotype or patient population, marking the end of the IFN-α era.