The recent development of direct‐acting antiviral (DAA) drugs has revolutionized the area of hepatitis C virus (HCV) therapeutics but the efficacy and clinical outcome of interferon (IFN)‐free therapy have not been extensively studied yet. We observed a dramatic increase in hypothyroidism among patients treated with sofosbuvir, IFN, and ribavirin. This is the first prospective study of the thyroid dysfunction in DAA drugs treated patients. This study compared the risk of hypothyroidism in two different groups of HCV patients treated with different DAA drugs regimens that were sofosbuvir + pegylated‐IFN‐α + ribavirin and sofosbuvir + daclatasvir + ribavirin. Our findings highlight the periodic screening of serum thyroid‐stimulating hormone and T4 levels in HCV infected patients during the treatment and posttreatment.