BackgroundEffective 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/designMulti-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.DiscussionThis 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 registrationDutch Trial Register, identifier: NTR5163. Registered on 17 April 2015; retrospectively registered during the recruitment phase.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-1950-3) contains supplementary material, which is available to authorized users.