Increasing evidence suggests that neuroimmune networks play key roles in the thymic histophysiology and pathology. Prompted by this, we analyzed by immunohistochemistry the distribution of human thymic cells expressing major neural and neuroendocrine markers and neural growth factor (NGF) receptors in combination with the expression patterns of various cytokeratins. Additionally, since some beta-tubulin isotypes are preferentially expressed in neuronal cells, the immunotopographical distribution of thymic cells expressing beta-tubulin II, III and IV was analyzed. Thymic epithelial cells (TECs) expressed protein gene product 9.5 (PGP 9.5), chromogranin A (CHRA), synaptophysin (SYN), neuron-specific enolase (NSE), tyrosine hydroxylase (TH), CD56, CD57, neurofilaments (NF) (140-160 kDa), NGF receptors (TrKA and p75), beta-tubulin II and IV isotypes and cytokeratin 7, 8, 10, 13, 14, 18 and 19. PGP 9.5 was preferentially expressed in cortical TEC whereas SYN, CHRA, NSE, TH and NF 140-160 kDa were preferentially expressed in medullary TECs and Hassal corpuscles. Variable levels of expression of beta-tubulin II and IV were observed in all TEC subtypes whereas beta-tubulin III was undetectable in TECs. Subcapsular and cortical TECs display higher expression of beta-tubulin IV and lower expression of beta-tubulin II in comparison to those observed in medullary TEC and Hassal corpuscles. The diversity of the immunotopographical distibution and the expression of neural and neuroendocrine markers, the NGF receptors TrKA and p75, and the beta-tubulin II and IV isotypes in the distinct subtypes of TEC may reflect the diversity of their biological functions and/or their different stages of differentiation. The present results provide further immunohistological evidence that numerous neural and neuroendocrine factors may be required for the development and function of the human thymic microenvironment.