||Objective:The observed poorer physical function in persons with mental disorders could partly be due to dys-regulation in physiological stress systems. However, an integrated picture of the role of physiological stresssystems on objective physical function is lacking. This study examined the association of multiple physiologicalstress systems with objective physical function, and explored whether these stress systems contribute to therelationship between depression/anxiety and poorer physical function.Methods:Data of 2860 persons of the Netherlands Study of Depression and Anxiety was used. Physical functionwas indicated by hand grip strength assessed using a hand-held dynamometer and lung function assessed using apeakflow meter. Inflammatory markers (CRP, IL-6, TNF-?), salivary cortisol (cortisol awakening response(AUCg, AUCi), evening cortisol) and ANS markers (heartrate, PEP, RSA) were determined. Depression/anxietydisorders were determined using psychiatric interviews. Linear regression analyses were adjusted for socio-demographics, health and lifestyle factors.Results:Higher inflammation levels were associated with lower hand grip strength (BCRP= -0.21(SE = 0.06),p< .001) and lower lung function (BCRP= -2.07(SE = 0.66),p= .002), BTNF-?=?3.35(SE = 1.42),p= .022). Higher salivary cortisol levels were associated with lower lung function (Beveningcortisol=?2.22(SE = 0.59),p< .001). The association, in women, between depression/anxiety disorders andpoorer physical function did not significantly diminish after adjustment for physiological stress markers.Conclusion:This large cohort study showed that stress system dysfunction (especially the immune-inflammatorysystem and HPA-axis) contributes to poorer objective physical function. Stress system dysfunction did not ex-plain the poorer physical function observed in persons with depression/anxiety disorders, suggesting that otherpathways are involved to explain that association.