Context Osteopathic physicians are trained to treat patients with musculoskeletal symptoms, to treat somatic dysfunction with osteopathic manipulative treatment (OMT), and to avoid unnecessarily prescribing drugs such as opioids. It is also generally believed that osteopathic physicians provide a unique patient-centered approach to medical care that involves effective communication and empathy. Such training and characteristics of osteopathic medical care (OMC) may enhance clinical outcomes among patients with chronic pain. Objectives The objectives of this study were to measure and compare the process and longitudinal outcomes of chronic low back pain (CLBP) treatment provided by osteopathic and allopathic physicians and to identify mediators of the treatment effects of OMC. Methods This retrospective cohort study was conducted utilizing adult participants with CLBP within the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation (PRECISION) from April 2016 through December 2022. Participants having an osteopathic or allopathic physician for at least 1 month prior to registry enrollment were included and followed at quarterly intervals for up to 12 months. Physician communication and physician empathy were measured at registry enrollment. Opioid prescribing and effectiveness and safety outcomes were measured at registry enrollment and for up to 12 months and were analyzed with generalized estimating equations to compare participants treated by osteopathic vs. allopathic physicians. Multiple mediator models, including physician communication, physician empathy, opioid prescribing, and OMT, with covariate adjustments, were utilized to identify mediators of OMC treatment effects. Results A total of 1,079 participants and 4,779 registry encounters were studied. The mean (SD) age of participants at enrollment was 52.9 (13.2) years, 796 (73.8 %) were female, and 167 (15.5 %) reported having an osteopathic physician. The mean physician communication score for osteopathic physicians was 71.2 (95 % CI, 67.6–74.7) vs. 66.2 (95 % CI, 64.8–67.7) for allopathic physicians (p=0.01). The respective mean scores for physician empathy were 41.6 (95 % CI, 39.9–43.2) vs. 38.3 (95 % CI, 37.6–39.1) (p<0.001). There was no significant difference in opioid prescribing for low back pain between osteopathic and allopathic physicians. Although participants treated by osteopathic physicians reported less severe nausea and vomiting as adverse events potentially attributable to opioids in a multivariable model, neither result was clinically relevant. OMC was associated with statistically significant and clinically relevant outcomes pertaining to low back pain intensity, physical function, and health-related quality of life (HRQOL) over 12 months. Physician empathy was a significant mediator of OMC treatment effects in each of the three outcome domains; however, physician communication, opioid prescribing, and OMT were not mediators. Conclusions The study findings indicate that osteopathic physicians provide a patient-centered approach to CLBP treatment, particularly involving empathy, that yields significant and clinically relevant outcomes pertaining to low back pain intensity, physical function, and HRQOL over 12 months of follow-up.