Across disciplines, prospective randomised controlled trials (RCTs) are the gold standard for comparative studies but have limited external validity and are typically conducted at substantial cost. Clinical registries provide access to large pools of real-world patients and infrastructure for collecting baseline variables, treatment and outcome data. Registry-based randomised controlled trials (rRCTs), most validated in the context of cardiology, are a promising new approach for conducting clinical trials. They combine the major strengths of conventional RCTs and clinical registries, and can also leverage existing clinical registry infrastructure for data collection. The Victorian Comprehensive Cancer Centre’s (VCCC) Registry Trials Program was initiated in early 2018 and aims to evaluate, to our knowledge, the first ever rRCTs in oncology. To date, four rRCTs across different tumour types (colorectal, glioblastoma, prostate and testicular cancers) have been initiated and are recruiting, with further studies in development. Key features of these rRCTs include simple, pragmatic study designs, the use of standard treatments that are readily available, and randomisation modules that link to existing comprehensive disease-specific registries. Questions being addressed include the optimal sequencing or duration of standard treatments, and head-to-head comparison of two standard of care approaches. Studies with quality of life endpoints and collecting patient reported outcomes have either been initiated or are planned. In this presentation, we describe the framework for these rRCTs and discuss challenges and opportunities for conducting rRCTs in the oncology setting.