Background/Aims: A deficit of various hormones during the process of aging and/or a heightened inflammatory state may be causally linked to the development of frailty. Phytoestrogens as weak estrogens, antioxidants, and anti-inflammatory agents may counteract this process. Methods: In a cross-sectional study including two cycles of the National Health and Nutrition Examination Survey (NHANES, i.e. 1999-2002), logistic regression was used to analyze the association between urinary concentrations of isoflavones and lignans and frailty in 600 females aged 50 years or older (median age 66.5 years). Participants were classified as 'frail' (meeting 3 or more of the 5 frailty criteria), 'prefrail' (meeting 1 or 2 of the criteria), or 'robust' (meeting none of the criteria). Four percent were frail. Results: For all of the phytoestrogens considered, the unadjusted OR were lower than 1 but generally not statistically significant aside from the association with O-desmethylangolensin (O-DMA) (OR = 0.76; 95% CI 0.61-0.92). Multivariate analysis did not attenuate this finding (OR = 0.74; 95% CI 0.61-0.90). Conclusions: This first analysis of the relationship between phytoestrogens and frailty revealed an inverse association between urinary O-DMA levels and frailty in women. However, the number of frail women was low. Although this finding may be confounded or biased, it seems worthwhile to intensify research on the potential preventive effects of O-DMA.