Background: The KEYNOTE-522 trial showed a significant improvement in pathological complete response (pCR) and event-free survival (EFS), leading to the FDA approval of pembrolizumab (pembro) combined with NACT for high-risk, early-stage TNBC. However, it utilized q3-week dosing for doxorubicin + cyclophosphamide (AC), not the ddAC regimen, which showed superior overall survival (OS) in the CALGB 9741 and EBCTCG trials. Consequently, the superiority of the KEYNOTE-522 regimen over ddAC remains uncertain. This retrospective case-control study compares TNBC patients treated with the KEYNOTE-522 regimen to controls treated with ddAC-NACT, reporting real-world efficacy and safety. Methods: Early-stage TNBC patients treated at our institute from Jan 2019 to Dec 2022 were included. Descriptive statistics outlined patient characteristics and clinicopathological data. Relative risk (RR) for pCR was calculated with a 95% confidence interval, and Kaplan-Meier estimated 1-year EFS and OS. Results: 97 patients were included, with 40 receiving pembro-NACT. Patient demographics and clinicopathological features didn't differ significantly, except for race (p = 0.047). Dose interruption was more common in the pembro group (p < 0.0001); nevertheless, most patients in both arms completed NACT and underwent surgery, mainly mastectomy. Immune-related adverse events reflected current reports. The pembro arm had a 1.43 times higher likelihood of pCR, but it didn't reach significance (RR=1.43, 95% CI: 0.89-2.28). Univariable associations between pCR and age, race, dose interruption, and dose of dexamethasone were not statistically significant; a multivariable model was not fitted for this reason. 1-year EFS and OS were not statistically different between the treatment arms (Table 1). Conclusions: In this real-world analysis, we observed a trend toward a higher rate of pCR in the KEYNOTE-522 compared to the ddAC regimen. Despite more dose interruptions with pembro, the 1-year EFS and OS were not significantly affected. While the more recent 5-year results from the KEYNOTE-522 trial have validated enhanced EFS, with OS data yet to mature, our findings didn't reveal clear short-term benefits. Larger studies are needed to assess long-term benefits, specifically in comparison to previously established standard therapies.