Context:Chronic inflammation may increase the risk of fracture, and omega-3 polyunsaturated fatty acids (PUFAs) may reduce fracture risk via down-regulation of inflammatory cytokine gene expression and other mechanisms.Objective:We investigated associations between baseline samples of inflammatory markers, TNFα soluble receptors 1 and 2 (TNFα-sR1 and -sR2), and incident hip fracture. These associations were then tested for effect modification by dietary PUFA intake estimated by a baseline food frequency questionnaire.Design and Setting:A nested case-control study was conducted among participants of the Women's Health Initiative Observational Study (ages, 50–79 y). Multivariable conditional logistic regression models were constructed to account for the paired design.Participants:This study sampled 400 pairs of hip fracture cases and controls without incident hip fracture, matched on age, year of enrollment, and menopausal hormone use.Main Outcome Measures:Odds ratio of hip fracture by quartile of TNF soluble receptors.Results:The odds ratio of hip fracture comparing the highest to lowest quartiles was 2.24 (95% confidence interval, 1.05–4.79; P for linear trend, .048) for TNFα-sR1 and 2.83 (95% confidence interval, 1.34–5.99; P for linear trend, .011) for TNFα-sR2, adjusted for FRAX hip fracture score, nutritional variables, and selected factors impacting inflammation; there was a gradient of risk by increasing quartile in TNFα-sR1. PUFA intake did not modify these associations.Conclusions:Women with the highest levels of TNFα-sR1 and TNFα-sR2 had a greater than 2-fold increased hip fracture risk, independent of other fracture risk factors. These associations did not differ by high vs low PUFA intake.