Introduction: Emerging data suggest that tomosynthesis mammograms (TS) are considerably superior to two-dimensional (2D) screening mammograms (2DMG) at reducing false positive biopsies for breast cancer screening. However, very little is reported about the comparative efficacy of the two modalities in the post-treatment setting. We compared the rate of downstream workup up after undergoing post-radiation screening 2DMG and TS following breast conservation therapy at our institution. Methods: Between the years 2011-2017, 712 breast cancer patients (range 31-91 years) were treated with lumpectomy and adjuvant radiotherapy. As per institutional standard, follow up included either screening 2DMG (n=569) or TS(n=143) and reviewed in this IRB-approved study. The primary endpoint for comparison was the rate of further imaging/workup post-treatment . Comparative analysis was conducted via multivariable binomial regression with propensity matching between the 2DMG and TS groups. Patients with clinical suspicion of recurrence otherwise were excluded. Results: The patient cohort in both groups included the following clinical characteristics,: 129 patients with ductal carcinoma in-situ (the remainder were invasive carcinoma; ductal or lobular). A total of 418 patients had T1 lesions, 143 T2, and 22 T3/T4. Eighty-five patients were node positive. Of those, 501 ER+/Her2-, 101 triple negative, and 96 triple positive. Adjuvant radiation included conventional fraction (457) or hypofractionation (153) with boost to the surgical cavity in523Accelerated Partial Breast Irradiation (APBI) was delivered in 106 patients. Post treatment scans occurred within 3 months (166), at 3-6 months (256), or 6+ months (281). The aforementioned characteristics were similarly distributed between 2DMG and TS groups, except for slightly more DCIS in the 2D group. There was a significantly higher proportion of patients that were recommended for immediate downstream workup in the 2D group (40.7%) compared to in the tomo group (16.8%) (HR = 3.40, P <0.001), leading to 12 biopsies in the 2D group (3 positive) and 4 biopsies in the TS group (0 positive). Upon multivariate analysis, the use of tomo was the lone correlate of reduced downstream workup (p < 0.05), although there was a trend toward significance in patients who were first imaged at a post-treatment interval of 6+ months and in patients not undergoing a radiation boost (P < 0.10). Conclusion: Post-breast conservation follow-up with tomo synthesis mammography resulted in significantly less downstream workup as compared to conventional 2D screening mammography. Further investigation is warranted to unveil the absolute and relative cost-effectiveness between the two modalities. Citation Format: Colosimo BL, Weinberger K, Hasan S, Gresswell S, Anderson S, Wegner RE, Trombetta M. Downstream workup after post-treatment mammography in breast conservation therapy: Is there a significant difference between tomosynthesis and 2-dimensional mammograms? [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 P6-02-05.