Background: Depression and anxiety are highly prevalent and often co-occur. Several studies indicate the potential of disorder-specific psychological interventions for the prevention of each of these disorders. To treat comorbidity, transdiagnostic treatment concepts seem to be a promising approach, however, evidence for transdiagnostic concepts of prevention remains inconclusive. Internet- and mobile-based interventions (IMIs) may be an effective means to deliver psychological interventions on a large scale for the prevention of common mental disorders (CMDs) such as depression and anxiety. IMIs have been shown to be effective in treating CMDs, e.g. in reducing symptoms of depression and anxiety. However, there is a lack of studies examining the efficacy of interventions reducing the incidence of CMDs. Moreover, the comparative cost-effectiveness of guided versus unguided IMIs for the prevention of depression and anxiety has not been studied yet. Hence, this study aims at investigating the (cost-) effectiveness of guided and unguided internet- and mobile-based transdiagnostic individually tailored indicated prevention of depression and anxiety. Methods: A multi-country three-armed randomized controlled trial will be conducted to compare a guided and unguided intervention to treatment as usual (TAU). Both active conditions are based on the same intervention, ICare Prevent, and differ only with regard to guidance format. Altogether, 954 individuals with subclinical symptoms of depression (CES-D ≥ 16) and anxiety (GAD-7 ≥ 5) who do not have a full-blown disorder will be recruited in Germany, Switzerland, Spain and the Netherlands, and randomized to one of three conditions (guided intervention, unguided intervention, or TAU). The TAU arm will receive access to the training after a 12-month waiting period. The primary outcome will be time to CMD onset (any depression/anxiety disorder) within a follow-up period of 12 months after baseline. Secondary outcomes will include disorder-specific symptom severity (depression/anxiety) assessed by diagnostic raters blinded to intervention condition at post-intervention, self-reports, acceptability, health related quality of life, and psychosocial variables associated with developing a CMD. Assessments will take place at baseline, mid-intervention (5 weeks into the intervention), post-intervention (8 weeks after randomization) and follow-up (6 and 12 months after randomization). Data will be analyzed on an intention-to-treat basis and per protocol. Cost-effectiveness will be evaluated from a public health and a societal perspective, including both direct and indirect costs. Discussion: The present study will further enhance the evidence-base for transdiagnostic preventive interventions and provide valuable information about optimal trade-off between treatment outcome and costs. Trial registration: German Clinical Trial Registration (DRKS - http://www.drks.de/drks_web/): DRKS00011099.