<p>Patients with muscle-invasive bladder cancer (MIBC) are often treated with platinum-based neoadjuvant chemotherapy (NAC). NAC-treated patients have higher odds of pathological downstaging than untreated patients on subsequent cystectomy and, consequently, improved survival. However, not all patients achieve pathological downstaging. Notably, luminal MIBC shows a superior pathological response to cisplatin-based NAC compared with non-luminal MIBC. This study aimed to examine the relationship between human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) status and the molecular subtypes of MIBC and to evaluate its role in the prediction of response to platinum-based neoadjuvant chemotherapy. We performed IHC for GATA binding protein 3 (GATA3), cytokeratin (CK) 5/6, p16, and synaptophysin to classify MIBC on transurethral resection of bladder tumor/biopsy specimens into molecular subtypes. We then examined the association between HER2 IHC status and the subtypes and its utility in predicting subsequent pathological responses. Out of 49 patients, HER2 IHC positivity (scores 2 + , 3 +) was predominantly observed in the genomically unstable (GU) immunohistochemical molecular subtype (GATA3 + , CK5/6–, p16 +), a surrogate of the luminal unstable transcriptomic subtype. Additionally, all but one patient with HER2-positive GU tumors (<i>n</i> = 8) had absent invasive tumor on subsequent cystectomy following cisplatin-based NAC. Conversely, all patients with HER2-negative (score 0, 1 +) GU tumors had residual invasive tumors. Finally, favourable outcome trends in recurrence-free and cancer-specific survival were observed with HER2 IHC positivity in this subtype. Overall, combining immunohistochemical molecular subtyping with HER2 IHC status may help predict responses to cisplatin-based NAC, guiding MIBC management decisions.</p>