EML4-ALK fusion genes have been recognized as novel "driver mutations" in a small subset of non-small cell lung cancers (NSCLC). The frequency of EML4-ALK fusions in NSCLC patients who have clinical characteristics related to EGFR mutation remains unknown. We screened 102 Chinese patients with NSCLC based on one or more of the following characteristics: female, no or light smoking history, and adenocarcinoma histology. EML4-ALK fusion genes were identified by RT-PCR, whereas EGFR (Exons 18-21) and KRAS (Exons 1 and 2) mutations were detected by DNA sequencing. Eight specimens (8%) were positive for EML4-ALK fusions, with seven being Variant 1 and one Variant 2. There were 44 (43%) and 17 (16%) patients harboring EGFR and KRAS mutations, respectively. Thirty-one (31%) cases were wild type for EML4-ALK, EGFR, and KRAS mutations. Of the eight patients with EML4-ALK, none had an EGFR mutation, whereas a KRAS mutation was detected in one patient. Histologically, five of the EML4-ALK positive tumors were adenocarcinoma and two were mixed adenosquamous carcinoma; only one was a squamous carcinoma. Our data support the conclusion that the EML4-ALK fusion gene defines a new molecular subset of NSCLC with distinct pathologic features.