We examined 53 invasive high-grade urothelial carcinomas (UCCs) and 42 paired lymph node metastases to determine frequency of HER2 overexpression, HER2/MYC coamplification, and association between HER2 and MYC status and clinicopathologic features. HER2 overexpression occurred in 19 UCCs (36%) and 14 metastases (30%), with an 88% concordance rate between UCCs and matched metastases. HER2 amplification occurred in 5 (10%) of 50 UCCs and 4 (11%) of 36 metastases, with a 100% concordance rate; MYC amplification occurred in 7 (18%) of 40 UCCs and 4 (13%) of 32 metastases, with a concordance rate of 50% between UCCs and metastases. Of 7 cases demonstrating HER2 amplification, MYC was coamplified in 4 (57%; P = .01), and coamplification was associated in all cases with metastasis and advanced local disease (pT4). Coamplification of HER2 and MYC occurs in a subset of patients with metastatic UCC. HER2 overexpression and amplification in metastatic lesions suggest that HER2-targeted therapy may be valuable for patients undergoing treatment for metastatic UCC, for which current therapy is limited. Further studies into the role of MYC coamplification in this population are needed to determine impacts on treatment with HER2-targeted therapy.