Background <p>We aimed to demonstrate that <i>MYC</i> amplification in adenocarcinomas of the stomach (GC) and gastroesophageal junction (GEJ) is of tumor biological significance and exhibits intratumoral heterogeneity.</p> Methods <p><i>MYC</i> amplification was analyzed by fluorescence in situ hybridization using whole mount tissue sections obtained from resection specimens of 460 chemotherapy naive (surgery only) and 122 neoadjuvantly treated GC-GEJs. The extent of intratumoral heterogeneity was quantified and a MYC score was established.</p> Results <p>The number of <i>MYC</i>-amplified tumor cells varied largely ranging from few scattered single cells (&lt; 20 per high power field) up to all tumor cells. MYC score 1 was found in 276 cases (47.4%). Split by cohorts, 199 (43.3%) tumors of the chemotherapy naïve (surgery only) and 77 (63.1%) tumors of the neoadjuvant cohort were sorted into the category MYC Score 1. These tumors were frequently located in the gastroesophageal junction, showed non-diffuse differentiation according to Lauren, and favored male sex. Additionally, correlations with higher T- and N category were observed. Overall survival and tumor-specific survival correlated negatively with the MYC score.</p> Conclusions <p><i>MYC</i> amplification is common in GC-GEJ, most often heterogeneously distributed, and associated with reduced therapy response. Most interestingly, <i>MYC</i> amplification is far more common in men, providing evidence for sex-specific disease mechanisms, and in tumors that show little response to neoadjuvant chemotherapy, suggesting a link to therapy resistance.</p>