Abstract: Objective: We evaluate change in low back pain (LBP) intensity and interference as the mechanism by which chiropractic care affects other biopsychosocial factors in US active-duty military members. Design: We conducted secondary, exploratory mediation analysis of pragmatic, multisite, clinical trial (NCT01692275) post results using natural effect modeling. Mediators were the 6-week values of Patient-Reported Outcomes Measurement Information System (PROMIS)-29 pain interference and intensity. Outcomes were 12-week values of other PROMIS-29 biopsychosocial subdomains. Models evaluated overall and individual factor contribution and were adjusted for baseline age, sex, LBP duration, LBP intensity and mediator and outcome values. Setting: Three US military treatment facilities. Participants: 750 US active-duty military members with LBP. Interventions: Trial participants received 6 weeks of treatment with chiropractic care plus usual medical care or usual medical care alone. Results: In multiple mediator models, pain interference and pain intensity explained much of the effect of chiropractic care on physical function (proportion mediated=0.77, 95% CI 0.43?to 2.0), fatigue (0.62, 95% CI 0.30?to 1.0), sleep disturbance (0.49, 95% CI 0.31?to 1.5) and social roles (0.81, 95% CI 0.50?to 2.0). Mental health was not evaluable due to the low prevalence of symptoms reported. The combined models of pain interference and pain intensity did not have a higher proportion mediated than the individual pain intensity models except for fatigue outcome models. Conclusion: Pain intensity appeared to be the mechanism by which much of the change in biopsychosocial factors occurred and should be considered a key clinical indicator for improvement in biopsychosocial health when chiropractic care is added to usual medical care for US active-duty military members.