This study was designed to clarify the function of caveolin-1 (Cav-1) in the development of lung cancer by investigating the mutation and protein expression of the Cav-1 gene in non-small cell lung carcinoma (NSCLC). Quantum dot immunofluorescence histochemistry was used to evaluate Cav-1 protein expression and subcellular localization in the lung cancer tissue microarray including 140 cases of lung cancer and 20 cases of non-cancerous lung tissue. Mutation of the Cav-1 gene in exon 1 and exon 3 was detected by polymerase chain reaction-single strand conformation polymorphism and sequencing. The positive rates of Cav-1 expression were 49.3% (69/140) in NSCLC group, significantly lower than the 100% (20/20) rate in the control group. Adenocarcinomas (16.7%), adenosquamous carcinomas (38.4%), squamous cell carcinomas (67.1%) and large cell lung cancers (66.7%) displayed Cav-1 positive staining, suggesting a gradient of Cav-1 expression according to tumor histotype-related aggressiveness. High-expression of Cav-1 protein was statistically correlated with pathologic TNM stage and lymph node metastasis. No mutation could be detected in exon 1 and exon 3 from all Cav-1 protein negative expression of NSCLC samples. Cav-1 immunoreactivity in lung cancer is histotype-dependent, increased Cav-1 expression indicates the malignant progression and high invasion features of NSCLCs. Deregulation of Cav-1 expression in NSCLCs may not correlate with mutation.