OBJECTIVE: To investigate the role of transforming growth factor beta 1 (TGF-beta 1), Smad3, and phospho-Smad3 (p-Smad3) in the invasion of somatotropinomas. METHODS: In total, 45 somatotropinomas were obtained from patients who underwent surgery for the first time between 2011 and 2015 at Beijing Tiantan Hospital. The expression of TGF-beta 1, Smad3, and p-Smad3 was examined by western blot, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry in somatotropinomas, and factors correlated with tumor invasion were analyzed. RESULTS: A total of 13 invasive somatotropinomas and 32 noninvasive somatotropinomas were enrolled in the study. TGF-beta 1 protein (P < 0.01) and mRNA (P < 0.01) levels were significantly less in the invasive somato-tropinom as than noninvasive somatotropinomas. There was no significant difference in Smad3 protein level or Smad3 mRNA level between invasive somatotropinomas and noninvasive somatotropinomas. However, the p-Smad3 protein level was significantly less in the invasive somatotropinomas than noninvasive somatotropinomas (P < 0.01). Univariate analysis demonstrated that TGF-beta 1 (P < 0.01) and p-Smad3 scores (P < 0.01) were associated with invasion. In multivariate analysis, p-Smad3 scores remained a significantly independent predictor of invasion (odds ratio 0.897, 95% confidence interval 0.834-0.964, P < 0.05). CONCLUSIONS: Low expression of p-Smad3 is correlated with invasion of somatotropinomas.