||Background: Auricular therapy is a promising treatment for pain. However, the physiologic mechanisms of analgesic effects are not well-understood, which limits the scientific credibility of auricular therapy for pain management. Objectives: This prospective, randomized clinical trial (RCT) was conducted to determine whether or not the levels of pro- and anti-inflammatory cytokines change in response to auricular point acupressure (APA) for chronic low-back pain (CLBP). Methods: Blood samples (10 mL) were collected in a vacutainer, based on standard phlebotomy procedures. Blood was drawn at the following timepoints: before APA treatment to measure the baseline; 30 minutes after the first APA treatment; weekly for 4 weeks; and within 1 month of a follow-up visit (a total of seven timepoints) for each subject). Results: Participants with CLBP reported a mean 70% reduction of pain intensity at the completion of the 4-week APA regimen. The participants also had changes in serum pro- and anti-inflammatory cytokines. In particular, interleukin (IL)-1?, IL-4, and IL-10 were decreased. IL-2, IL-6, and tumor necrosis factor (TNF)-? were increased. In contrast, the participants who were in the sham APA group, with a 29% pain reduction, had a different profile. In particular, I-L2, IL-4, and TNF-? were decreased. IL-1?, IL-6, and IL-10 were increased. IL-1?, IL-2, IL-6, and IL-10 levels were associated with the worst pain intensity score, suggesting that these cytokines had an important role in mediating the APA effect on CLBP. Conclusions: The changes in cytokine levels in response to APA treatment suggested that APA could influence the level of circulating cytokines in patients with CLBP.