Background A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin still represents standard treatment of chronic hepatitis C infection in the majority of patients. However, it is not established which of the two licensed peginterferon products, peginterferon alpha‐2a or peginterferon alpha‐2b, is the most effective and has a better safety profile. Objectives To systematically evaluate the benefits and harms of peginterferon alpha‐2a versus peginterferon alpha‐2b in head‐to‐head randomised clinical trials in patients with chronic hepatitis C. Search methods We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until October 2013. We also searched conference abstracts, journals, and grey literature. Selection criteria We included randomised clinical trials comparing peginterferon alpha‐2a versus peginterferon alpha‐2b given with or without co‐intervention(s) (for example, ribavirin) for chronic hepatitis C. Quasi‐randomised studies and observational studies as identified by the searches were also considered for assessment of harms. Our primary outcomes were all‐cause mortality, liver‐related morbidity, serious adverse events, adverse events leading to treatment discontinuation, other adverse events, and quality of life. The secondary outcome was sustained virological response in the blood serum. Data collection and analysis Two authors independently used a standardised data collection form. We meta‐analysed data with both the fixed‐effect and the random‐effects models. For each outcome we calculated the relative risk (RR) with 95% confidence interval (CI) based on intention‐to‐treat analysis. We used domains of the trials to assess the risk of systematic errors (bias) and trial sequential analyses to assess the risks of random errors (play of chance). Intervention effects on the outcomes were assessed according to GRADE. Main results We included 17 randomised clinical trials which compared peginterferon alpha‐2a plus ribavirin versus peginterferon alpha‐2b plus ribavirin in 5847 patients. All trials had a high risk of bias. Very few trials reported data on very few patients for the patient‐relevant outcomes all‐cause mortality, liver‐related morbidity, serious adverse events, and quality of life. Accordingly, we were unable to conduct meta‐analyses on all‐cause mortality, liver‐related morbidity, and quality of life. Twelve trials reported on adverse events leading to discontinuation of treatment without clear evidence of a difference between the two peginterferons (197/2171 (9.1%) versus 311/3169 (9.9%); RR 0.84, 95% CI 0.57 to 1.22; I2 = 44%; low quality evidence). A trial sequential analysis showed that we could exclude a relative risk reduction of 20% or more on this outcome. Peginterferon alpha‐2a significantly increased the number of patients who achieved a sustained virological response in the blood serum compared with peginterferon alpha‐2b (1069/2099 (51%) versus 1327/3075 (43%); RR 1.12, 95% CI 1.06 to 1.18; I2= 0%, 12 trials; moderate quality evidence). Trial sequential analyses supported this result. Subgroup analyses based on risk of bias, viral genotype, and treatment history yielded similar results. Trial sequential analyses supported the results in patients with genotypes 1 and 4, but not in patients with genotypes 2 and 3.