Recent investigations support the presence of human somatostatin (SS) in the excretory system of the human lacrimal gland. To get deeper insights into a possible role of SS at the ocular surface and in the lacrimal apparatus, we investigated the distribution pattern of SS and its receptors 1–5 (SSTR1-5) by means of RT-PCR, real-time RT-PCR, Western blot and immunodot blot analysis as well as immunohistochemistry in lacrimal gland, tear fluid, conjunctiva, cornea, nasolacrimal duct epithelium, and conjunctival (HCjE) and corneal (HCE) epithelial cell lines. Cell culture experiments with HCjE and HCE were performed to analyze a possible impact of SS and inflammatory mediators on the regulation of SSTR. The results confirmed the presence of SS in lacrimal gland and tear fluid, whereas it was absent at the protein level in all other tissues and cell lines investigated. Expression of SSTR1, -2, and -5 was detectable in lacrimal gland, conjunctiva, cornea, and nasolacrimal ducts. HCjE expressed only hSSTR1 and -2, and HCE revealed only SSTR2. SSTR3 and -4 were not detected in any of the analyzed samples or cell lines. In vitro on cultured immortalized HCjE cells SS leads to a concentration-dependent down-regulation of SSTR1 mRNA but does not affect SSTR2 mRNA expression. Relative expression of SSTR1 and -2 is differentially modulated by proinflammatory cytokines and bacterial components, suggesting that the expression of both receptors is immunomodulated. Our data support an autocrine and paracrine role of SS in the lacrimal system and at the ocular surface and implicate a role of SS in corneal immunology.