Many patients with stage I nonsmall cell lung carcinoma will develop recurrence after surgical excision. Sox2 is a marker of embryonic stem cell pluripotency that is associated with aggressive tumor behavior and is expressed in a subset of lung adenocarcinomas. We hypothesized that Sox2 expression may provide prognostic information in early stage lung adenocarcinomas. We evaluated formalin-fixed, paraffin-embedded tissue from 104 stage I lung adenocarcinomas resected between 1997 and 2000. Sox2 expression was analyzed by immunohistochemistry and compared with clinicopathologic features, time-to-progression, and overall survival (OS). Sox2 expression was detected in 50% of the cases and was more frequent in tumors from older and male patients but not significantly associated with smoking status, tumor stage, grade, or histologic subtype. Compared with Sox2-negative tumors, Sox2 expression predicted a shorter time-to-progression (49% vs. 82% at 5 y; P=0.0006) and shorter OS (54% vs. 79% at 5 y; P=0.004). By multivariate analysis, Sox2 expression predicted a greater risk of progression among men [hazard ratio (HR) 5.6; 95% confidence interval (CI) 2.3-13.8] and women (HR 2.1; 95% CI 0.8-5.7). Sox2 expression was associated with significantly shorter OS among men (HR 2.5; 95% CI 1.2-5.1), but not in women. Sox2 seems to be an independent predictor of poor outcome in stage I lung adenocarcinomas and may help stratify patients at increased risk for recurrence.