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ObjectiveTo investigate the effect of protease inhibitors (PIs)- or non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based therapy on the progression of hepatitis C in patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection. MethodsA total of 273 patients initially diagnosed with HCV/HIV coinfection were enrolled and divided into PIs group (n=135) and NNRTIs group (n=138) to receive PIs-based therapy and NNRTIs-based therapy, respectively, for one year. Laboratory indices, such as HCV RNA, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBil), albumin (Alb), laminin (LN), cholyglycine (CG), type III procollagen (PCIII), type IV collagen (CIV), prothrombin activity (PTA), and cholinesterase (CHE), were quantified before and after treatment. The obtained data were analyzed using SPSS 11.5 software; enumeration data were analyzed using the Kolmogorov-Smirnov test, and non-normal data were analyzed using the Mann-Whitney U test. ResultsAfter the end of treatment, PTA, CHE, TBil, Alb, ALT, AST, CG, and LN levels were significantly higher in NNRTIs group than in PIs ［PTA: 77% (67%-109%) vs 68% (56%-91%); CHE: 6717.00 U/L (5951.00-7622.00 U/L) vs 586200 U/L (4392.00-8539.25 U/L); TBil: 10.95 μmol/L (8.10-14.32 μmol/L) vs 8.60 μmol/L (8.00-9.50 μmol/L); Alb: 43.90 mmol/L (39.65-48.20 mmol/L) vs 38.90 mmol/L (36.00-45.00 mmol/L); ALT: 52.50 U/L (30.00-93.50 U/L) vs 36.20 U/L (30.30-40.40 U/L); AST: 49.00 U/L (33.00-80.00 U/L) vs 31.30 U/L (29.70-38.70 U/L); CG: 16.78 μg/ml (3.26-29.32 μg/ml) vs 3.26 μg/ml (102-688 μg/ml); LN: 34.40 ng/ml (16.71-46.54 ng/ml) vs 34.05 ng/ml (33.42-64.33 ng/ml); P＜0.01 or P＜0.05］. ConclusionNNRTIs-based therapy can accelerate the progression of hepatitis C in HCV/HIV-coinfected patients.