We conducted a systematic review and meta-analysis to compare the screening performance of synthesized mammography (SM) plus digital breast tomosynthesis (DBT) with digital mammography (DM) plus DBT or DM alone. Methods: Medline, Embase, Web of Science, and the Cochrane Library databases were searched from January 2010 to January 2021. Eligible population-based studies on breast cancer screening comparing SM/DBT with DM/DBT or DM in asymptomatic women were included. A random-effect model was used in this meta-analysis. Data were summarized as risk differences (RDs), with 95 % confidence intervals (CIs). Results: Thirteen studies involving 1,370,670 participants were included. Compared with DM/DBT, screening using SM/DBT had similar breast cancer detection rate (CDR) (RD ¼ À0.1/1000 screens, 95 % CI ¼ À0.4 to 0.2, p ¼ 0.557, I 2 ¼ 0 %), but lower recall rate (RD ¼ À0.56 %, 95 % CI ¼ À1.03 to À0.08, p ¼ 0.022, I 2 ¼ 90 %) and lower biopsy rate (RD ¼ À0.33 %, 95 % CI ¼ À0.56 to À0.10, p ¼ 0.005, I 2 ¼ 78 %). Compared with DM, SM/DBT improved CDR (RD ¼ 2.0/1000 screens, 95 % CI ¼ 1.4 to 2.6, p < 0.001, I 2 ¼ 63 %) and reduced recall rate (RD ¼ À0.95 %, 95 % CI ¼ À1.91 to À0.002, p ¼ 0.049, I 2 ¼ 99 %). However, SM/DBT and DM had similar interval cancer rate (ICR) (RD ¼ 0.1/1000 screens, 95 % CI ¼ À0.6 to 0.8, p ¼ 0.836, I 2 ¼ 71 %) and biopsy rate (RD ¼ À0.05 %, 95 % CI ¼ À0.35 to 0.24, p ¼ 0.727, I 2 ¼ 93 %). Conclusions: Screening using SM/DBT has similar breast cancer detection but reduces recall and biopsy when compared with DM/DBT. SM/DBT improves CDR when compared with DM, but they have little difference in ICR. SM/DBT could replace DM/DBT in breast cancer screening to reduce radiation dose.