Objective To investigate the association between plasma trans fatty acids (TFAs) and bone mineral density (BMD) and risk of fracture among US adults. Furthermore, we have evaluated the impact of inflammation on this relationship. Methods Participants (the National Health and Nutrition Examination Survey) with measured data on BMD and TFAs were included. TFAs were measured by gas chromatography–mass spectrometry and BMD was measured using dual-energy x-ray absorptiometry densitometers. Results Of the 4022 eligible participants, 48.1% were men. The mean age of the population sample was 44.6 years. In the model adjusted for age, sex, race, education, income, physical activity, smoking, fasting blood glucose, systolic and diastolic blood pressure, body mass index, diabetes, and hypertension, across the increasing quartiles (Q) of individual plasma TFAs, BMD decreased for most of the sites measure: for example, Q1 vs. Q4 1.04 vs. 0.095 g/cm2 for palmitelaidic acid and 1.11 vs. 0.099 g/cm2 for elaidic acid (all p < 0.001). In models using the same adjustment, linear regression displayed a significant negative association between plasma TFAs and BMD for most of the sites measured (all p < 0.001). Moderation analysis revealed that inflammation [assessed as a serum C-reactive protein (CRP)] was not significantly implicated in the relationship between BMD and TFAs. There was no significant difference in percentage of fractures (hip, spine, wrist) observed across quartiles of plasma TFAs (all p > 0.125). Conclusions Our findings highlight, for the first time, the potentially detrimental impact of plasma TFAs on bone health that does not appear to be moderated through inflammation.