<jats:title>Abstract</jats:title><jats:p>Activating mutations in the tyrosine kinase domain of the <jats:italic>HER2</jats:italic> gene have recently been reported in lung adenocarcinomas, mainly in East Asian patients. Our study was devised to evaluate the prevalence and nature of <jats:italic>HER2</jats:italic> mutations in lung adenocarcinomas from Caucasian patients. The mutational status of the <jats:italic>HER2</jats:italic> gene was evaluated in 403 lung adenocarcinomas by PCR‐single strand conformation polymorphism analysis and direct sequencing of Exons 19 and 20. We found <jats:italic>HER2</jats:italic> mutations in 9 (2.2%) cases. Seven (78%) of the mutations were in frame duplications/insertions at codons 776–779 (YVMA), the other 2 were base substitutions resulting in aminoacid changes. The hotspot mutation at bases 776–779 was previously found to be the most frequent <jats:italic>HER2</jats:italic> mutation in Asiatic patients. The distribution of mutations was significantly different between conventional lung adenocarcinomas (CLAs) and lung adenocarcinomas with bronchioloalveolar features (ABAFs). Seven (6.2%) of 113 ABAFs and 2 (0.7%) of 290 CLA were mutated (<jats:italic>p</jats:italic> = 0.0025). In addition, the frequency of <jats:italic>HER2</jats:italic> mutations was slightly higher in females (4.1%) than in males (1.8%) and in never smokers (3.1%) than in smokers (1.9%), but differences were not statistically significant. This series of tumors was also investigated for EGFR and <jats:italic>K‐ras</jats:italic> mutations. EGFR mutations were observed in 43 (10.7%) cases, and <jats:italic>K‐ras</jats:italic> mutations in 110 (27.3%) cases. <jats:italic>EGFR</jats:italic>, <jats:italic>HER2</jats:italic> and <jats:italic>K‐ras</jats:italic> mutations were found to be mutually exclusive events. The presence of <jats:italic>HER2</jats:italic> mutations in a subset of patients with lung adenocarcinoma raise hope to treat these patients with <jats:italic>HER2</jats:italic> specific kinase inhibitors. © 2006 Wiley‐Liss, Inc.</jats:p>