Background Although several studies proved that SM could substitute for FFDM, the efficacy of SM in microcalcification evaluation remains controversial. Aims To investigate the diagnostic performance of synthetic mammography (SM) in the evaluation of microcalcifications in comparison with full-field digital mammography (FFDM). Methods In this retrospective study, 76 mammograms of 76 patients who underwent FFDM and digital breast tomosynthesis (DBT) acquisitions concomitantly between 2018 and 2019 and whose final mammography interpretation revealed microcalcifications (28 malignant microcalcifications and 48 benign microcalcifications) were included. All mammograms were reviewed independently by three radiologists with different levels of breast imaging experience. Readers were blinded to patient outcomes and interpreted each case in two separate reading sessions (first FFDM, second SM + DBT), according to the BI-RADS lexicon. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated using ROC analysis in all cases for FFDM and SM + DBT sessions. The readers also assigned conspicuity scores to mammograms. The interobserver agreement was calculated using intraclass correlation coefficients (ICC). Results The overall AUCs for malignant microcalcifications were 0.80 (95% CI: 0.75-0.85) in FFDM and 0.85 (95% CI: 0.80-0.89) in SM, and no significant difference was found between the groups (p = 0.0603). The sensitivity of the readers increased slightly with experience. The ICC values of BI-RADS categorization between readers were 0.93 (95% CI: 0.90-0.95) and 0.94 (95% CI: 0.91-0.96) for FFDM and SM, respectively. Conclusions SM had similar diagnostic performance in the evaluation of breast microcalcifications in comparison with FFDM, regardless of reader experience levels.