Introduction: This study investigated the systemic response of serum bone alkaline phosphatase (SBAP) and urinary N-telopeptide (UNTX) to tobacco exposure and environmental tobacco smoke (ETS) and the possible effect modification (and variability) of this response by racial/ethnic origin. Methods: Data (n=5411) were obtained from the National Health and Nutrition Examination Survey, with data analysis done on adults aged ≥ 20years. Outcome variables were SBAP and UNTX. Independent variable was tobacco exposure measured using serum cotinine levels and adjusted for covariates. Generalized linear models were used to explore associations. Results: A percentage increase in log transformed serum cotinine was associated with a 0.005 percentage increase in log transformed SBAP (CI: 0.002, 0.008) and 0.02 percentage increase in log transformed UNTX (CI: −0.01, 0.04) with interaction between cotinine and race/ethnicity (p=0.01). Stratifying by race/ethnicity, tobacco exposure was associated with significant decreases in UNTX among non-Hispanic Whites–0.008(−0.014, −0.002) and Mexican Americans −0.014 (−0.025, −0.002) only. Categories of serum cotinine were associated with a monotonic increase in SBAP (p for trend <0.001) and monotonic non-linear decrease in UNTX (p for trend>0.05). Conclusions: Tobacco and environmental tobacco exposure are associated with SBAP and increased bone formation. The response of UNTX to these exposures is modified by race/ethnicity with non-Hispanic Whites and Mexican-Americans less sensitive to the resorptive effects of tobacco exposure on bone.