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Background: Depression and anxiety are among the most prevalent mental health issues experienced worldwide. However, whereas cross-cultural studies utilize psychometrically valid and reliable scales, fewer can meaningfully compare these conditions across different groups. To address this gap, the current study aimed to psychometrically assess the Brief Symptomatology Index (BSI) in 42 countries., Methods: Using data from the International Sex Survey (N = 82,243; M age  = 32.39; SD age  = 12.52; women: n = 46,874; 57 %), we examined the reliability of depression and anxiety symptom scores of the BSI-18, as well as evaluated evidence of construct, invariance, and criterion-related validity in predicting clinically relevant variables across countries, languages, genders, and sexual orientations., Results: Results corroborated an invariant, two-factor structure across all groups tested, exhibiting excellent reliability estimates for both subscales. The 'caseness' criterion effectively discriminated among those at low and high risk of depression and anxiety, yielding differential effects on the clinical criteria examined., Limitations: The predictive validation was not made against a clinical diagnosis, and the full BSI-18 scale was not examined (excluding the somatization sub-dimension), limiting the validation scope of the BSI-18. Finally, the study was conducted online, mainly by advertisements through social media, ultimately skewing our sample towards women, younger, and highly educated populations., Conclusions: The results support that the BSI-12 is a valid and reliable assessment tool for assessing depression and anxiety symptoms across countries, languages, genders, and sexual orientations. Further, its caseness criterion can discriminate well between participants at high and low risk of depression and anxiety., Competing Interests: Declaration of competing interest JBurkauskas works as a consultant at Cronos. MNP discloses that he has consulted for and advised Game Day Data, Addiction Policy Forum, AXA, Idorsia, Baria-Tek, and Opiant Therapeutics; been involved in a patent application involving Novartis and Yale; received research support from the Mohegan Sun Casino, Children and Screens and the Connecticut Council on Problem Gambling; consulted for or advised legal, gambling and non-profit entities on issues related to impulse control, internet use and addictive behaviors; conducted clinical evaluations related to impulse-control and addictive behaviors; performed grant reviews; edited journals/journal sections; given academic lectures in grand rounds, CME events and other clinical/scientific venues; and generated books or chapters for publishers of mental health texts. The views presented in this manuscript represent those of the authors and not necessarily those of the funding agencies. The rest of the authors report no conflicts of interest with respect to the content of this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)