BACKGROUND: Gastric cancer (GC) is histologically a very heterogeneous disease, and the temporal development of different histological phenotypes remains unclear. Recent studies in lung and ovarian cancer suggest that KRAS activation (KRASact) can influence histological phenotype. KRASact likely results from KRAS mutation (KRASmut) or KRAS amplification (KRASamp). The aim of the study was to investigate whether KRASmut and/or KRASamp are related to the histological phenotype in GC. METHODS: Digitized haematoxylin/eosin-stained slides from 1282 GC resection specimens were classified according to Japanese Gastric Cancer Association (JGCA) and the Lauren classification by at least two observers. The relationship between KRAS status, predominant histological phenotype and clinicopathological variables was assessed. RESULTS: KRASmut and KRASamp were found in 68 (5%) and 47 (7%) GCs, respectively. Within the KRASmut and KRASamp cases, the most frequent GC histological phenotype was moderately differentiated tubular 2 (tub2) type (KRASmut: n = 27, 40%; KRASamp: n = 21, 46%) or intestinal type (KRASmut: n = 41, 61%; KRASamp: n = 23, 50%). Comparing individual histological subtypes, mucinous carcinoma displayed the highest frequency of KRASmut (JGCA: n = 6, 12%, p = 0.012; Lauren: n = 6, 12%, p = 0.013), and KRASamp was more frequently found in poorly differentiated solid type (n = 12, 10%, p = 0.267) or indeterminate type (n = 12, 10%, p = 0.480) GC. 724 GCs (57%) had intratumour morphological heterogeneity. CONCLUSIONS: This is the largest GC study investigating KRAS status and histological phenotype. We identified a relationship between KRASmut and mucinous phenotype. The high level of intratumour morphological heterogeneity could reflect KRASmut heterogeneity, which may explain the failure of anti-EGFR therapy in GC.