Purpose To identify factors associated with the development of adverse drug reactions (ADR) in ribavirin therapeutic regimens. Methods A multicenter, prospective study was conducted in three public health hospitals in Rio de Janeiro between November 2015 and March 2018. Inclusion criteria were defined by patient follow‐up at pharmaceutical consultation at the time of drug dispensing as those who used sofosbuvir in combination with simeprevir, daclatasvir, and/or ribavirin. All patients were invited to participate in the study during the first interview. Adverse drug reactions were reported according to the treatment regimen and frequency of occurrence. Statistical analysis was used to compare adverse reactions between treatments and their associated factors. Results A total of 405 patients were included in the study (mean age 59.6 ± 9.6 years); 61.0% were female, 88.1% were infected with genotype 1, and 65.4% were cirrhotic. The most prescribed treatment was the combination of sofosbuvir, daclatasvir, and ribavirin (55.3%). The majority of patients reported at least one ADR during treatment (83.2%), of which fatigue, anemia, and headache were the most common. Being female (OR = 1.86, [1.08‐3.20]) and use of ribavirin (OR: 2.39; 95% CI [1.38‐4.13]) were predictors for the development of ADR, which was also associated with development of anemia (OR: 10.28; 95% CI: [5.78‐18.30]). Treatment efficacy was 98.1%. Conclusions Direct‐acting antiviral has been shown to be safe and effective. Therefore, use of ribavirin is questionable due to associated adverse reactions and similar efficacy to other treatments.