Abstract Introduction: Diagnostic metastatic staging imaging (SI) for asymptomatic stage I-II patients (pts) is not routinely recommended, but is warranted in stage II-III pts with high risk biological subtypes, where previous trials have shown up to a 15% rate of de novo metastatic disease. NCCN guidelines endorse CT CAP and bone scan (STD) for stage III pts, but not PET/CT, and PET/CT is not covered in most parts of the country. We present data on the performance and value of PET/CT. Methods: Data were available for 799 high risk clinical stage II-III pts screened for I-SPY2 at UCSF, Uminn, UAB, and Georgetown. Of these, 564 pts ranging in age from 25-81 (median = 48) had complete records that were retrospectively reviewed for SI and potential false positives (FP), defined as incidental findings on SI proven benign by subsequent workup. Economic evaluation was conducted from the payer perspective using the mean national 2018 Medicare Physician Fee Schedule and representative costs from the UCSF billing department. The incremental cost effectiveness ratio (ICER) measured the cost of using PET/CT per percent patient (pt) who avoided a FP. Results: The rate of de novo metastatic disease was 4.8% (38/799), range 3.6-6.4%. Of the 564 pts with complete records, diagnostic SI varied significantly among the four sites (p < 0.0001). STD was used for most pts at UAB (92.8%, 141/152) and Georgetown (85.7%, 54/63), while PET/CT was used for most pts at UCSF (86.6%, 226/261) and Uminn (63.6%, 56/88). Chest X-ray was used for 29.5% (26/88) at Uminn. There were significantly more pts with FP in the group that received STD (22.1%, 51/231) vs. PET/CT (11.1%, 33/298) (p < 0.05). Mean time between incidental finding on SI to determination of FP was 10.8 days. When controlling for institution, mean time from cancer diagnosis to initiation of neoadjuvant chemotherapy was significantly different between STD (44.3 days) and PET/CT (37.5 days) groups (p < 0.05). When aggregating the four sites using mean costs from the 2018 Medicare Physician Fee Schedule, the mean cost/pt was $1132 for STD vs. $1477 for PET/CT. The mean increase in price from baseline SI costs due to FP workup was $216 (23.6%) for STD vs. $65 (4.6%) for PET/CT. The ICER was $31 per percent pt who avoided a FP. When analyzing UCSF pts alone using representative reimbursements from Medicare, the mean cost/pt was $1236 for STD vs. $1081 for PET/CT; using representative reimbursements from Anthem Blue Cross, the mean cost/pt was $3080 for STD vs. $1662 for PET/CT. The ICERs were -$10 and -$95 per percent pt who avoided a FP, respectively. Conclusion: As compared to STD metastatic staging workup, PET/CT added value by decreasing FP two-fold. This reduced direct costs of FP workup procedures that took a mean time of 10.8 days to resolve. PET/CT also accelerated treatment start. Reducing the chance of FP workup for metastatic disease is of enormous value to pts. Our data establish the value of PET/CT for staging in our high risk clinical stage II-III trial population and highlight the need for alignment between hospital pricing strategies and payer coverage policies in order to deliver high value care to pts. Citation Format: Hyland CJ, Varghese F, Yau C, Beckwith H, Khoury K, Varnado W, Hirst G, Chien J, Yee D, Isaacs C, Forero-Torres A, Esserman L, Melisko M, I-SPY2 Consortium. The use of 18F-FDG PET/CT as an initial staging procedure for stage II-III breast cancer reduces false positives, costs, and time to treatment: A multicenter value analysis in the I-SPY2 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-15-01.