The histologic heterogeneity of lung adenocarcinoma creates a variety of complex challenges to pathologists in analyzing the various subtypes. Current classification schemas do not take into account the major subtype. We analyzed 100 cases for clinical, pathologic, and molecular features using a modification of the 2004 World Health Organization (WHO) classification to record the major component in the mixed subtype tumors. The tumors were analyzed for KRAS mutation and epidermal growth factor receptor (EGFR) by mutation, chromogenic in situ hybridization, and immunohistochemistry for EGFR and phosphorylated EGFR. Gene expression analysis was performed using HG-U133A Affymetrix oligonucleotide microarrays revealing 3 gene clusters. The most common major histologic subtype was papillary (37%) followed by acinar (30%), solid (25%) and bronchioloalveolar (7%) carcinoma (BAC), although no pure BACs were seen. Sixteen tumors harbored EGFR mutations and 14 KRAS mutations. Papillary adenocarcinoma strongly correlated with EGFR mutation (P<0.001) and gene profile Cluster 1 (P=0.006) with weaker correlations with low grade (P=0.038) and favorable behavior in Stage 1 patients (P=0.047). Micropapillary subtype correlated strongly with EGFR mutation (P<0.001) and weakly with Cluster 1 (P=0.030). Solid adenocarcinoma strongly correlated with gene profile Cluster 3 (P=0.001) and worse survival (P=0.001). BAC as a major component strongly correlated with gene Cluster 2 (P=0.001). Cluster 1 correlated strongly with less smoking (P<0.001), papillary histology (P<0.001), and EGFR mutations (P<0.001). Cluster 3 strongly correlated with heavier smoking (P<0.001), larger tumor size (P<0.001), solid subtype (P<0.001), and poor grade (P=0.004); weak correlations were found with KRAS mutation (P=0.025). No correlation was found with BAC and EGFR by mutation, chromogenic in situ hybridization or immunohistochemistry. Higher stage (P<0.001), grade (P<0.001), and solid subtype (P=0.001) correlated with shorter survival. Our data suggest that EGFR mutations are associated with papillary adenocarcinoma and gene profile Cluster 1. We discovered this only because we used a comprehensive approach examining in detail all histologic subtypes and we modified the 2004 WHO mixed subtype to include the major histologic subtype. As we do not know the major genetic pathways of 30% to 70% of lung adenocarcinomas, the comprehensive histologic subtyping we propose gives advantage for recognition of unanticipated histologic-genetic correlations that might not be detected using classification systems that focus primarily on specific aspects of adenocarcinomas such as BAC or EGFR mutations. Such an approach should be considered in future studies for validation in other datasets.