Hepatitis C virus (HCV) infection is increasingly seen as a major public health problem, threat, and concern worldwide. In Yemen about 1.7% of the population is infected with chronic hepatitis C. This study aimed to detect the predictors for response to pegylated interferon and ribavirin (Peg-IFN/RBV) in chronic HCV Yemeni patients. The study was conducted on 100 patients with chronic HCV who received Peg-IFN/RBV in the 48th Military Hospital in Sana'a Yemen, from 2011 to 2013. All patients were subjected to complete history taking, thorough clinical examinations, routine laboratory investigation, and abdominal ultrasonography. The HCV RNA was assessed at week 72 of treatment to detect whether the patient achieved sustained virological response (SVR). The SVR was achieved in 64% of the samples. Age above 40, Khat chewing, and obesity were the sociodemographic factors that predict good response for Peg-IFN/RBV combined therapy. Platelet count, alpha feto-protein (AFP), aspartate transaminase (AST), and alanine transaminase (ALT) levels were the basic laboratory investigations that gave favorable response. Significant predictors of sustained response included: older than 40 years (OR = 0.136, P = 0.042), Khat chewer (OR = 0.016, P = 0.008), body mass index (BMI) (OR = 0.055, P = 0.029) and increase in fasting blood glucose (OR = 0.925, P = 0.004), alkaline phosphatase (OR = 0.969, P = 0.001), total and bilirubin (OR = 0.058, P = 0.017), AST (OR = 1.033, P = 0.002), and albumin (OR = 6.490, P = 0.021). Studying the independent variables of response, we revealed that male gender, BMI, ALT >40, AFP >10, viremia >600, and hemoglobin and thyroid stimulating hormone (TSH) levels are variables associated with failure of end of treatment response (ETR) and SVR.