Background: Taxane and platinum (TP) NAC regimens, e.g. Carboplatin and Docetaxel (CbD), in TNBC are currently of great interest, having good pathologic complete response (pCR) rates but with a significantly more manageable toxicity profile compared to anthracycline-based NAC regimens. Forkhead Box C1 (FOXC1), a transcriptional driver of cell plasticity/partial EMT/metastasis is an established mesenchymal marker diagnostic of basal-like breast cancer having proven prognostic value, but of uncertain predictive value. We sought to evaluate the potential of FOXC1 in predicting pCR to neoadjuvant TP regimens in patients diagnosed with TNBC. Methods: Pre-NAC tumor biopsy FOXC1 mRNA expression status was correlated with rate of pCR in a pooled, ambispective cohort (prospective cohort GEICAM/2006-03, NCT00432172 pooled with multi-institutional retrospective cohort, n = 119). A specific FOXC1 mRNA expression cutoff value was derived to maximize Negative Predictive Value (NPV) and Sensitivity for pCR prediction. The pCR-predictive ability of FOXC1 mRNA expression was then assessed in two validation cohorts of evaluable patients who had been enrolled in prospective clinical trials (UCONN/FIOCRUZ, n = 222, HGUGM, NCT01560663, n = 221). All evaluated patients had been diagnosed with TNBC and had received a Taxane plus Platinum-based NAC regimen. Results: FOXC1 mRNA expression was associated with pCR in CbD/TP treated TNBC patients with pCR rates of 43.48%, 47.89% and 52.73% observed in the discovery and two validation cohorts (two tailed T-test p-values of 0.0005, 0.002, 0.009, respectively). FOXC1 expression above the pre-determined cutoff value was associated with pCR to CbD/TP NAC in patients diagnosed with TNBC in both validation cohorts (OR 4.894, 1.504-15.924; p = 0.004 and OR 2.293, 1.208-4.352; p = 0.006). Conclusions: We report the retrospective validation of pre-NAC breast cancer biopsy FOXC1 mRNA expression for predicting efficacy of CbD/TP NAC in two independent, prospectively accrued TNBC patient cohorts. The described strategy may be acceptable for patient stratification to guide CbD/TP NAC recommendations in TNBC. FOXC1 mRNA or protein expression, assessed using qRT-PCR or routine immunohistochemistry (IHC), respectively, could potentially be utilized in future fixed-arm/adaptive clinical trials to further optimize NAC efficacy, in terms of achieved pCR rates, and to extend disease-free survival in patients diagnosed with TNBC.