Background Panretinal photocoagulation (PRP) has been the standard of care for patients with proliferative diabetic retinopathy (PDR) for the last 40 years. It prevents severe visual loss in PDR but is also associated with adverse effects on visual functions. Objectives The clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (CLARITY) trial evaluated the clinical efficacy, mechanisms and cost-effectiveness of intravitreal aflibercept (Eylea^®, Regeneron, Tarrytown, NY, USA/Bayer Pharma AG, Berlin, Germany therapy for PDR. Design A multicentre, prospective, individually randomised, single-masked, active-controlled trial with concurrent economic evaluation that tested the non-inferiority of intravitreal aflibercept versus standard care PRP at 52 weeks. A subset of the participants enrolled in a mechanistic evaluation substudy. Setting 22 UK NHS clinical sites. Participants Patients aged at least 18 years having either treatment-naive PDR or active retinal neovascularisation (NV) despite prior PRP requiring treatment and best corrected visual acuity (BCVA) of 54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or better in the study eye were included. Eyes with evidence of macular oedema at baseline confirmed by central subfield thickness > 320 µm on spectral-domain optical coherence tomography were excluded. Intervention In the intervention arm, intravitreal aflibercept injections were given at baseline, 4 and 8 weeks and patients were subsequently reviewed every month and injected pro re nata based on the treatment response defined by degree of regression of retinal NV. In the comparator arm, PRP was completed in 2-weekly sessions and then supplemented if necessary at 8-weekly intervals. Main outcome measures The primary outcome was the mean change in BCVA at 52 weeks utilising a linear mixed-effects model incorporating data from both week 12 and week 52. Results A total of 232 participants (116 per arm) were recruited between August 2014 and November 2015. A total of 221 and 210 participants contributed to the intention-to-treat (ITT) model and per-protocol (PP) analysis, respectively. Economic evaluation was undertaken on 202 participants (101 per arm) with complete cost and outcome data. Aflibercept was non-inferior and superior to PRP in both the ITT population [mean BCVA difference 3.9 letters, 95% confidence interval (CI) 2.3 to 5.6 letters; p < 0.0001] and the PP population (difference 4.0 letters, 95% CI 2.4 to 5.7 letters; p < 0.0001). From a public sector multiagency perspective that covers health and social care services, treatment with aflibercept costs more in terms of total resource use (mean adjusted total additional cost per patient = £5475, bootstrapped 95% CI £5211 to £5750) than PRP over a 12-month follow-up period. There were a small number of important safety events in each arm. Patients were more satisfied with aflibercept than PRP. Limitations This study is limited to 1 year of follow-up. Conclusions At an additional cost, the study shows that intravitreal aflibercept is an effective alternative treatment option for PDR in the first year. Future work Future research is needed to evaluate the long-term benefits of aflibercept in comparison with PRP and other anti-vascular endothelial growth factor agents for this condition. Trial registration Current Controlled Trials ISRCTN32207582. Funding This project was funded by the National Institute for Health Research (NIHR) Efficacy and Mechanistic Evaluation programme, a Medical Research Council and NIHR partnership. Aflibercept was supplied by Bayer Plc (Reading, UK). The study was sponsored by NIHR Moorfields Biomedical Research Centre and supported by the UK Clinical Research Network. The research was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, the NIHR Moorfields Clinical Research Facility and the UK Clinical Reasearch Collaboration-registered King’s Clinical Trials Unit at King’s Health Partners, which is partly funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London.