Background Alongside a clinical and research setting, whole body magnetic resonance imaging (WB-MRI) is increasingly offered as a direct-to-consumer screening service. Data is needed on the clinical relevance of findings and associated psychological impact of such screening. Therefore, we conducted a prospective follow-up study to provide insight in the effectiveness and psychological impact of direct-to-consumer screening using both WB-MRI and cardiological examination. Methods and findings The study population consisted of 3603 voluntary, primarily middle-aged participants who underwent commercial WB-MRI and cardiological screening at one of 6 study clinics in Germany or the Netherlands between July 2014 and March 2016. MRI investigation consisted of directed scans of the brain, neck, abdomen and pelvis. Cardiovascular examination included pulmonary function, resting electrocardiogram, transthoracic echocardiogram and a bicycle exercise stress test. Findings were assessed by experienced radiologists and cardiologists. In addition, participants were inquired about several (psychological) domains, including the expectations and consequences of the screening procedure. Out of 3603 individuals, 402 (11.2%) demonstrated abnormal MRI (n = 381) and/or cardiological findings (n = 79) for which they were advised to undergo further consultation <3 months in regular healthcare. In 59.1% of cases of abnormal MRI findings which were consulted, fully completed consultations were available in 87.1%. After consultation, 77.6% of initial MRI outcomes were adopted. In 40.9% of cases of abnormal MRI findings, recommendations for consultation were not adhered to during the study period. 71.1% of adopted MRI-findings required treatment or monitoring, including 19 malignancies. For abnormal cardiological findings, 70.9% of cases were consulted in regular healthcare. Of these, 91.1% had a completed follow-up procedure of which 72.5% of initial findings were adopted and 83.8% of these findings required treatment or monitoring. The most frequently reported psychological consequences of the screening procedure were getting reassurance (72.0%) and insight into one’s own health status (83.0%). 5.0% reported to feel insecure about their health and 6.2% worried more about their health as a consequence of screening. Main limitations of the study were considered the telephonic follow-up of referred clients and the heterogeneity of screening equipment and assessment of radiologists and cardiologists. Conclusions Direct-to-consumer screening using whole-body MRI and cardiological testing is feasible and effective for the detection of clinically relevant and treatable abnormalities. Psychological harm was not frequently reported in study participants.