The drug options and strategies for treatment against hepatitis C virus (HCV) infection have changed considerably in the last few years. The aim of this study was to compare the changes in the proportion of nonresponders and patients who achieved a sustained virologic response (SVR) from 1999 to 2015 in one single cohort. A total of 522 patients treated against chronic hepatitis C were included prospectively. The time periods were 1999-2002 [interferon (IFN)/ribavirin (RBV)], 2002-2009 (pegylated-IFN/RBV), 2010-2011 (use of IL28B genotype), 2012-2014 (pegylated-IFN/RBV/direct-acting antivirals) and 2015 (IFN-free direct-acting antiviral-based therapy). The numbers of nonresponders in the study periods in chronological order were as follows: 14 (40%), 76 (21.3%), 7 (8%), 10 (13%), and 0; P=1.1×10 and r=0.837. The corresponding numbers of patients who achieved SVR were 9 (25.7%), 14 (40.9%), 44 (50.6%), 51 (66.2%), and 64 (90.1%), P=3.3×10 and r=0.997. Characteristics that may impair SVR, such as advanced fibrosis, genotype 1 infection, HIV coinfection, or treatment experience, did not decrease in the last time periods. The proportion of nonresponders was significantly reduced using the IL28B genotype as a predictive tool and direct-acting antivirals further improved treatment outcome. Concomitantly, the rates of SVR showed a linear increase.