A single-nucleotide polymorphism (SNP) in the FGFR4 gene is associated with poor prognosis in solid tumors. A recent study presented the first evidence that FGFR4 Arg388 could predict resistance to adjuvant chemotherapy in breast cancer. The present study evaluates the potential of this SNP to predict response to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC).As part of a randomized phase II trial, 257 patients received either doxorubicin-cyclophosphamide (AC) or doxorubicin-pemetrexed (AP) followed by docetaxel (Doc; Taxotere) as NCT for T2-4/N0-2/M0 PBC. FGFR4 genotype analyzed on germline DNA was correlated with clinicopathologic variables, clinical response, and pathological complete response (pCR) using univariate and multivariate analyses.Only axillary lymph node status was associated with FGFR4 Arg388 [odds ratio (OR) 1.82, P = 0.03]. Joint analysis of both treatment arms revealed a correlation of FGFR4 Arg388 with clinical response (OR 2.14, P = 0.03) but not with pCR. In the AC-Doc arm, however, FGFR4 Arg388 was a strong predictor of pCR in the multivariate analysis (OR 3.79, P = 0.03). A significant interaction between FGFR4 genotype and treatment (P = 0.01) was found, indicating a therapy-specific effect.We provide the evidence that FGFR4 388Arg is an independent predictor of pCR following AC-Doc as NCT in PBC.