Background: Effective interventions for young adults with severe, multiple problems - such as psychosocial and psychiatric problems, delinquency, unemployment and substance use - are scarce but urgently needed in order to support an adequate transition to adulthood. A multimodal day treatment program called "New Opportunities" (in Dutch: "De Nieuwe Kans"; DNK) was specifically developed to target multi-problem young adults in The Netherlands. The aim of this study protocol is to describe the design of a randomized controlled trial (RCT) in clinical practice to examine the effectiveness of DNK in comparison with care as usual (CAU). Methods/design: Multi-problem young adults in Rotterdam, The Netherlands, will be assigned randomly to DNK (expected N = 150) and CAU (expected N = 150). Primary outcome measures are recidivism and self-sufficiency. Secondary outcome measures include quality of life, attending school/work, psychological functioning, cognitive distortions and substance use. Participant and program characteristics will be examined as potential moderators of effectiveness. Additionally, cost-effectiveness will be measured. During 14 months, data from multiple resources will be collected at four time points. Discussion: This study is one of the first RCTs on the effectiveness of interventions developed for multi-problem young adults. The results will contribute to the currently scant knowledge about what works for various multi-problem young adults in their transition to adulthood. In addition, the study protocol will provide insight into implementing an RCT in a dynamic setting of clinical practice. Trial registration: Dutch Trial Register, identifier: NTR5163. Registered on 17 April 2015; retrospectively registered during the recruitment phase.