Aurora kinase A (AURKA) gene amplification has been documented in 67% of hormone-naive prostate cancer cases that progress to a highly aggressive variant of castrate-resistant disease, clinically referred to as "neuroendocrine" prostate cancer, "small cell" prostate carcinoma, or "anaplastic" prostate cancer. Therefore, AURKA amplification is a potential prognostic biomarker that may help to identify patients with prostate cancer who are at high risk for developing castrate-resistant disease with clinical features of small cell carcinoma. Furthermore, AURKA inhibitors are currently being tested in clinical trials. In a previous study, we found AURKA amplification in 6 cases of prostate cancer with Paneth cell-like cells. This morphologic pattern has been suggested to represent low-grade neuroendocrine differentiation (NED) with generally favorable prognosis. We sought to investigate the frequency of AURKA amplification and the histologic characteristics of prostate cancer with Paneth cell-like NED. Twenty-five cases from 172 prostatectomies were evaluated for the presence of 18 morphologic features and AURKA amplification. Most prostate cancers with Paneth cell-like NED had macronucleoli (92%), basophilic appearance (88%), perineural invasion (72%), and nuclear stratification (76%). The frequency of AURKA amplification was 45%, present throughout the examined tumor nodule including areas without Paneth cell-like cells. When histologically similar cases with and without AURKA amplification were compared, this gene alteration was associated with larger extent of Paneth cell-like NED identified at magnification ×20 (P = .015), higher percentage of Paneth cell-like NED throughout the tumor nodule (P = .033), ductal features (P = .02), and higher overall Gleason grade (P = .039). AURKA amplification was not associated with age, serum prostate specific antigen, or tumor stage. The high frequency of AURKA amplification (45%) in localized prostate cancer with Paneth cell-like NED and its potential prognostic significance warrant further investigation.