12004 Background: The majority of head/neck (HN) patients who undergo radiotherapy develop RIX. Unfortunately, existing treatments are of limited benefit and have side effects. Initial small studies suggest acupuncture may treat chronic RIX. A multicenter, phase III, randomized, sham-controlled trial (NCT02589938) was conducted to compare true acupuncture (TA) with sham acupuncture (SA) and wait list control (WLC) group in treating chronic RIX. Methods: HN patients with chronic RIX at least 12 months post-RT were recruited through the WF NCORP RB network (2UG1CA189824). Patients must have received bilateral radiation therapy with subsequent grade 2 or 3 xerostomia per modified RTOG scale, with no history of xerostomia or other illness known to affect salivation prior to HN XRT. All patients received standard oral hygiene and were randomized to TA, SA, or WLC. Patients in TA and SA were treated 2 times per week for 4 weeks. Those experiencing a marginal response (10-19 point decrease on the Xerostomia questionnaire (XQ)) received another 4 weeks of the respective treatment. Patients who had no response (increase in XQ score or decrease of < 10 points from baseline), partial response (20 or more point decrease in XQ score from baseline), or complete response (XQ score = 0) did not receive further treatment. Patient outcomes including XQ and FACT-HN were collected at baseline, 4, 8, and 12 weeks; the primary endpoint was XQ at 4 weeks. A sample size of 80 per group (240 total), had 80% power to detect a difference of 10 points between groups, assuming two-sided alpha = 0.013 and 20% attrition. Analysis of covariance adjusted for baseline XQ and Bonferroni corrections for pairwise comparisons. Results: 258 from 33 different practices participated. Average age was 65 years, 78% male, and 67% had AJCC stage IV a,b disease. At week 4, there was a group main effect on the XQ (P = 0.02) revealing significant between group differences between TA and WLC (51.1 vs 56.8, P = 0.008), with marginal between group difference between TA and SA (51.1 vs 54.5, P = 0.066) and no difference between SA and WLC (P = 0.36). A similar pattern was seen at week 8 (TA = 48.3, SA = 50.8, WLC = 54.8; only TA vs WLC significant, P = 0.012) and 12 (TA = 48.6, SA = 49.3.8, WLC = 54.6; TA vs WLC, P = 0.02; SA vs WLC, P = 0.04; TA vs SA, P = 0.79). Incidence of clinically significant RIX (XQ scores > 30) followed a similar pattern. The FACT-HN at week 12 revealed statistically and clinically significant group differences for the total score and several subscales between TA vs SA and WLC with no differences between SA and WLC. Completer and mediation analyses will be presented. Conclusions: True acupuncture was more effective in treating chronic RIX and improving QOL one or more years after the end of XRT than sham acupuncture or standard oral hygiene. Clinical trial information: NCT02589938.