Sox2 is a transcription factor that regulates embryonic stem cell pluripotency and drives commitment of airway precursor cells to basal-type and neuroendocrine cells in the developing lung. In cancer, Sox2 has been associated with a "stemness" phenotype that predicts for poor outcomes. We examined Sox2 expression in pulmonary neoplasms with respect to tumor type and differentiation, in comparison with conventional markers. Immunohistochemistry for Sox2, p63, CK5/6, and thyroid transcription factor-1 was performed on 121 tumors, including 34 adenocarcinomas (ACA), 32 squamous cell carcinomas (SCC), 14 typical carcinoids, 12 atypical carcinoids, 14 large cell neuroendocrine carcinomas, and 15 small cell carcinomas. Sox2 was strongly, diffusely expressed in 91% of SCC and 21% of ACA. Ninety-four percent of SCC coexpressed Sox2 and p63; 1 case was only focally positive for p63 but diffusely positive for Sox2. Twenty-nine percent of ACA were at least focally p63+; 12% were Sox2+/p63+. All of the ACA diffusely positive for Sox2 were p63 negative. Among non-small cell lung carcinoma overall, there was a significant association between Sox2+/p63- expression and high-grade histology (P = 0.02). Strong Sox2 expression was detected in 23% of low-grade and 72% of high-grade neuroendocrine carcinomas (P = 0.0004). Sox2 is highly expressed in concert with p63 in most SCC, but may also influence tumor differentiation in both non-small cell lung carcinomas and pulmonary neuroendocrine tumors.