Abstract Introduction: A synthetic 2D mammogram (C-view) can be created by combining the individual optimally enhanced 1mm slices of a digital breast tomosynthesis (DBT). Studies show that screening with 2D mammography and DBT increases the cancer detection rate by about 40% and reduces the recall rate by about 25% but it doubles the x-ray exposure to the patient and reading time for the radiologist compared to standard 2D screening. The use of a synthetic 2D instead of a standard 2D film may theoretically overcome these problems by avoiding a second exposure and presenting the detail normally available in DBT in one picture. The hypothesis we wished to test is, "if the synthetic 2D is normal/benign, is there any advantage in also viewing the DBTs?" Method: We prospectively collected data on 2500 unselected cases presenting symptomatically or at follow up, all of whom underwent DBT on a Hologic® Dimensions machine. From the 3D data sets synthetic 2D mammograms were constructed (Hologic C-view). One breast radiologist with 13 years experience of interpreting mammograms and 5 years with DBTs was asked to review the 2D synthetic mammograms (CC and MLO) and report them before then reviewing the DBTs and issuing a final report. The mammograms were reported M1 to M5 using the standard BIRADs criteria. The BIRADs scores for each breast were recorded prospectively. Similarly the breast density as assessed by eye was recorded (fatty/average density/dense). Results: 2500 patients were studied between October 2013 and October 2014. The average age of the women was 58.4 years (range 28-95). Of these some were under follow up after mastectomies so in total there were 4589 individual mammogram sets reported. Table 1 summarises the correlation between the synthetic 2D and DBT reports. BIRADS Classification - Synthetic 2D v DBT Synthetic 2D M1M2M3M4M5 M115874000 M2827051510DBTM32810140 M4015480 M5001396 The correlation is very close, but there were 11 patients in whom the synthetic 2D was reported normal or benign (M1 or M2) but the DBT was reported as M3. Of these 10 were benign on assessment and one malignant. There was one patient reported as M2 on synthetic 2D but M4 on DBT. Assessment confirmed malignancy. Sixteen cases reported as suspicious of malignancy (M3/4) by synthetic 2D were subsequently downgraded to benign after review of the DBT. We estimate that 2D mammography alone would have detected only 68 of the 94 detected by synthetic 2D. Of the 4589 examinations, 1131 (25%) were assessed as fatty, 1851 (40%) as average density and 1607 (35%) as dense. One cancer was missed in an averagely dense and one in a dense breast. Conclusion: In a symptomatic and follow up clinic, our study suggests that much radiologist's time and x-ray exposure to the patient could be saved by using synthetic 2D mammograms rather than using 2D/3D combinations. Only if the synthetic 2D is reported M3, 4 or 5 is it necessary to review the DBT. Whilst a similar trial is required to confirm these findings in a screening population, this trial suggests that synthetic 2D mammography could be cost effective compared to combination 2D/3D. Citation Format: Holt SD, Sharaiha YM, Moalla A, Williams HR, Thomas D, Huws AM. A comparison of the diagnostic performance of 2D synthetic mammography versus digital breast tomosynthesis in 2500 patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-09.