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Background: Multi-national studies in the association between handgrip strength and depression in middle and older aged adults are limited. Hence, Brazil, China, Europe, Korea, United Kingdom (UK) and United States (US) datasets were utilized to investigate this association., Methods: A cross-sectional study was conducted with 51,285 participants aged >45 years. Handgrip strength scores were divided into quartiles, groups 1 (highest) to 4 (lowest) in each database, and depression measures converted to binary scores., Results: Males in China and UK reported higher adjusted odds ratios (aORs) of depression for groups 2, 3, and 4 than for group 1. Brazil, US, and Korea reported greater aORs in groups 3 and 4 whereas Europe demonstrated increased aORs for group 4 only. Among females, China, Brazil, US, and Korea showed high aORs across all groups, while UK and Europe reported increased aORs for group 4 only. Highest ORs were reported from Korea in group 4 for males (aOR: 3·09; 95 % CI: 2·15-4·43; p < 0·001) and females (aOR: 3·74; 95 % CI: 2·78-5·03; p < 0·001). When removing the regional factor, aORs were higher in lower groups, with the highest reported from group 4 for males (aOR: 2·32; 95 % CI: 2·09-2·58; p < 0·001) and females (aOR: 2·11; 95 % CI: 1·95-2·29; p < 0·001)., Limitations: Being a cross-sectional study, the results were not able to establish the causal direction between handgrip strength and depression., Conclusion: Lower handgrip strength was associated with an increased likelihood of depression. Early assessment of handgrip strength may identify populations at-risk for depression among middle and older aged adults., Competing Interests: Conflict of interest Dr Marco Solmi has received honoraria and has been a consultant for Angelini, Lundbeck, Otsuka. All other authors declare they have no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)