We analyzed relationships between histological subtypes of pulmonary adenocarcinomas and three gene alterations (p53, K-ras, and epidermal growth factor receptor gene), or thyroid transcription factor-1 (TTF-1) expression, and also studied prognoses by the subtypes, with or without combined multiple gene mutation status. Our purpose was to clearly determine pathogenesis, along with the best predictive value for biology and therapy-related traits. A total of 223 consecutively resected pulmonary adenocarcinomas were sub-classified using either the World Health Organization (WHO) or our five-cell type (FCT) classification system (hobnail, columnar/cuboidal, mixed, polygonal/oval, and goblet cell types). DNAs extracted from frozen samples of the adenocarcinomas were examined for gene alterations, and TTF-1 expressions were determined using immunohistochemistry. Next, relationships among the various data and clinicopathological factors were analyzed. The most striking result was: while almost 70% of adenocarcinomas were sub-classified as a mixed subtype by WHO, the FCT classified many of them as other cell subtypes. The FCT closely reflected differences in etiological factors, cellular lineages, and frequencies of gene mutations; and whether the data from combined gene mutations were used or not, differences among the cell types in postoperative survivals appeared. In contrast, subtypes of WHO did not show any association with the gene alteration or prognosis, and the FCT more suitably indicated sensitivity to gefitinib therapy than did WHO. The FCT combined with multiple gene mutation status appears to be useful in indicating pathogenesis and predicting the biological nature of pulmonary adenocarcinomas, and it could facilitate development of new therapies for each subtype.