BACKGROUND: To identify candidate inflammatory biomarkers for the underlying mechanism of auricular point acupressure (APA) on pain relief and examine the correlations among pain intensity, interference, and inflammatory biomarkers. DESIGN: This is a secondary data analysis. METHODS: Data on inflammatory biomarkers collected via blood samples and patient self-reported pain intensity and interference from three pilot studies (chronic low back pain, n = 61; arthralgia related to aromatase inhibitors, n = 20; and chemotherapy-induced neuropathy, n = 15) were integrated and analyzed. This paper reports the results based on within-subject treatment effects (change in scores from pre- to post-APA intervention) for each study group (chronic low back pain, cancer pain), between-group differences (changes in scores from pre- to post-intervention between targeted-point APA [T-APA] and non-targeted-point APA [NT-APA]), and correlations among pain intensity, interference, and biomarkers. RESULTS: Within-group analysis (the change score from pre- to post-APA) revealed statistically significant changes in three biomarkers: TNF-α (cancer pain in the APA group, p = .03), β-endorphin (back pain in the APA group, p = .04), and IL-2 (back pain in the NT-APA group, p = .002). Based on between-group analysis in patients with chronic low back pain (T-APA vs NT-APA), IL-4 had the largest effect size (0.35), followed by TNF-α (0.29). A strong positive monotonic relationship between IL-1β and IL-2 was detected. CONCLUSIONS: The current findings further support the potential role of inflammatory biomarkers in the analgesic effects of APA. More work is needed to gain a comprehensive understanding of the underlying mechanisms of APA on chronic pain. Because it is simple, inexpensive, and has no negative side effects, APA can be widely disseminated as an alternative to opioids.