Diffuse gastric cancer, characterized by poorly cohesive, diffusely infiltrating cells with no or little gland formation, is known to show several morphologic variants, but their prognostic value, if any, is poorly documented. In this article, 119 cases of invasive (T1b to T4) diffuse gastric cancer, which had undergone potentially curative surgery and were followed postoperatively for a median time of more than 10 years, were investigated for histologic or histochemical patterns possibly predictive of survival. Among 5 histologic groups identified, a low-grade subtype (17 cases) with prominent desmoplasia closely surrounding individual tumor cells (tumor embedding desmoplasia) and no or scarce angio-lympho-neuroinvasion showed stage-independent improved survival compared with 36 non-low-grade desmoplastic, 24 signet ring, and 28 diffuse cancers not otherwise specified. Fourteen cases with anaplastic cells showed clinicopathologic patterns and outcome of highly malignant neoplasms. None of the tumor cell differentiation markers (including 6 mucins and 3 proteases) nor proliferative index or p53 protein expression had independent predictive power, although MUC1 was significantly less expressed in low-grade desmoplastic cases. Cox survival analysis showed the significantly better prognosis of 17 low-grade desmoplastic and worse prognosis of 14 anaplastic cancers compared with the remaining 88 cases. In conclusion, a low-grade desmoplastic and a high-grade anaplastic subtype should be separated histologically from the bulk of diffuse gastric cancers owing to their distinctive histologic, clinicopathologic, and prognostic aspects.