BACKGROUND CONTEXT: Low back pain (LBP) is a common and significant cause of disability worldwide, however; questions about cause still remain. PURPOSE: To investigate the association between LBP, body mass index (BMI), and moderate to vigorous physical activity (MVPA) in a twin sample. STUDY DESIGN: Cross sectional study of monozygotic (MZ) and dizygotic (DZ) twins from the Washington State Twin Registry. PATIENT SAMPLE: Monozygotic and dizygotic twins from the Washington State Twin Registry. OUTCOME MEASURES: Self-report measures: Low back pain, body mass index, duration and intensity of exercise. METHODS: The sample included 5,183 same-sex pairs (69% MZ). The outcome was self-reported diagnosis of LBP from a health care provider. A phenotypic model tested the association between BMI and LBP without including genetic or shared environmental confounds. We then re-estimated the association using a quasi-causal model which controls for those confounds. Finally, we used a mediation model to investigate if the association between LBP and MVPA was mediated by BMI. RESULTS: In the phenotypic regression of LBP on BMI, there was a similar to 4-fold increase in the odds of having LBP with every one-unit increase in BMI (odds ratio [OR] =3.83; 95% confidence interval =3.28, 4.46). However, quasi-causal regression of LBP on BMI was reduced to zero (OR =0.95; 95% confidence interval =0.60, 1.49). A significant genetic background to BMI and LBP was present (b(A) =1.66; p<.001), even after controlling for confounders. In another analysis there was a significant direct effect between MVPA and LBP (b(p)=-0.092, standard error [SE] =0.017, p<.001). In mediation analysis, the effect of MVPA on LBP was partially mediated through MVPA effects on BMI (b(PMVPA)=-0.043, SE=0.003, p<.001) and BMI effects on LBP (b(PBMI)=1.281, SE=0.079, OR=3.6, p<.001), however shared environmental factors confounded this relationship. CONCLUSIONS: BMI was not associated with LBP, despite sharing a phenotypic association, but they may share a genetic influence. The effect of MVPA on LBP is, in part, mediated by BMI but shared environment confounds this relationship. (C) 2020 Elsevier Inc. All rights reserved.