Background: There is a growing consensus about the importance of mental health screening of youths in welfare and juvenile justice institutions. The Massachusetts Youth Screening Instrument-second version (MAYSI-2) was specifically designed, normed and validated to assist juvenile justice facilities in the United States of America (USA), in identifying youths with potential emotional or behavioral problems. However, it is not known if the USA norm-based cut-off scores can be used in Switzerland. Therefore, the primary purpose of the current study was to estimate the diagnostic performance and optimal cut-off scores of the MAYSI-2 in a sample of Swiss youths in welfare and juvenile justice institutions. As the sample was drawn from the French-, German- and Italian-speaking parts of Switzerland, the three languages were represented in the total sample of the current study and consequently we could estimate the diagnostic performance and the optimal cut-off scores of the MAYSI-2 for the language regions separately. The other main purpose of the current study was to identify potential gender differences in the diagnostic performance and optimal cut-off scores., Methods: Participants were 297 boys and 149 girls (mean age = 16.2, SD = 2.5) recruited from 64 youth welfare and juvenile justice institutions (drawn from the French-, German- and Italian-speaking parts of Switzerland). The MAYSI-2 was used to screen for mental health or behavioral problems that could require further evaluation. Psychiatric classification was based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL). The MAYSI-2 scores were submitted into Receiver-Operating Characteristic (ROC) analyses to estimate the diagnostic performance and optimal 'caution' cut-off scores of the MAYSI-2., Results: The ROC analyses revealed that nearly all homotypic mappings of MAYSI-2 scales onto (cluster of) psychiatric disorders revealed above chance level accuracy. The optimal 'caution' cut-off scores derived from the ROC curve for predicting (cluster of) psychiatric disorders were, for several MAYSI-2 scales, comparable to the USA norm-based 'caution' cut-off scores. For some MAYSI-2 scales, however, higher optimal 'caution' cut-off scores were found., Conclusions: With adjusted optimal 'caution' cut-off scores, the MAYSI-2 screens potential emotional or behavioral problems well in a sample of Swiss youths in welfare and juvenile justice institutions. However, as for choosing the optimal 'caution' cut off score for the MAYSI-2, both language as well as gender seems to be of importance. The results of this study point to a compelling need to test the diagnostic performance and optimal 'caution' cut-off scores of the MAYSI-2 more elaborately in larger differentiated language samples in Europe.