In order to confirm 14-3-3 sigma (σ) protein distribution in human tissues, immunohistochemistry was performed using various paraffin-embedded human tissues. In normal human tissues, the strongest immunoreactivity for 14-3-3σ protein was observed in squamous epithelia at various sites, followed by basal cells of the trachea, bronchus and basal or myoepithelial cells of various glands. Moderate to weak 14-3-3σ immunoreactivity was seen in the epithelial cells of the alimentary tract, gall bladder, urinary tract and endometrium. In the lung, 14-3-3σ immunoreactivity was also observed in hyperplastic type II alveolar cells and metaplastic squamous cells. Immunohistochemical study using non-small-cell lung cancers revealed that 14-3-3σ immunoreactivity was stronger in squamous cell carcinomas than in adenocarcinomas. The present study revealed that 14-3-3σ expression was exclusively present in various epithelial cells and had a tendency to be stronger in cells destined for squamous epithelium or differentiating toward squamous cells in human normal and neoplastic cells.