Background Although clinical peer review is a well-established instrument for improving quality of care, clinical effectiveness is unclear. Methods In a pragmatic cluster randomised controlled trial, we randomly assigned 60 German Initiative Qualitätsmedizin member hospitals with the highest mortality rates in ventilated patients in 2016 to intervention and control groups. The primary outcome was hospital mortality rate in patients ventilated fore more than 24 hours. Clinical peer review was conducted in intervention group hospitals only. We assessed the impact of clinical peer review on mortality using a difference-in-difference approach by applying weighted least squares (WLS) regression to changes in age-adjusted and sex-adjusted standardised mortality ratios (SMRs) 1 year before and 1 year after treatment. Recommendations for improvement from clinical peer review and hospital survey data were used for impact and process analysis. Results We analysed 12 058 and 13 016 patients ventilated fore more than 24 hours in the intervention and control hospitals within the 1-year observation period. In-hospital mortality rates and SMRs were 40.6% and 1.23 in intervention group and 41.9% and 1.28 in control group hospitals in the preintervention period, respectively. The groups showed similar hospital (bed size, ownership) and patient (age, sex, mortality, main indications) characteristics. WLS regression did not yield a significant difference between intervention and control groups regarding changes in SMRs (estimate=0.04, 95% CI= −0.05 to 0.13, p=0.38). Mortality remained high in both groups (intervention: 41.8%, control: 42.1%). Impact and process analysis indicated few perceived outcome improvements or implemented process improvements following the introduction of clinical peer review. Conclusions This study did not provide evidence for reductions in mortality in patients ventilated for more than 24 hours due to clinical peer review. A stronger focus on identification of structures and care processes related to mortality is required to improve the effectiveness of clinical peer review.