Background/objective: Radiotherapy (RT) is commonly used to treat advanced malignant tumors of the head and neck. Despite modern RT techniques adjacent unaffected tissues are irradiated. Besides early reactions, these normal tissues can evince late radiation effects resulting in both functional impairments and morphologic alterations (tissue remodeling, e.g., parenchymal atrophy, fibrosis, cellular infiltrations, and repair processes). We set out to characterize the histologic pattern of the late effects of radiation following a clinically relevant RT protocol, paying particular attention to the integrity-supporting cytokeratins (CK) / intermediate filament proteins (IF) and the basement membrane proteins (BM). Methods: In 120 Wistar rats examined in two studies we investigated the effects on the major salivary glands (SG) and laryngotracheal tissues depending on radiation dose (fractionated irradiation, 2 Gy per day, total dose of 20, 40 or 60 Gy), time since radiation (less than 4 months to 1 year) and animal age (3 months to 2 years) using histologic methods (hematoxylin-eosin staining). Additionally, we examined the expression profile and distribution pattern of CK/IF (CK 5/6, 8, 13, 13-15/16, 17/19, 18, vimentin) and BM or BM-associated protein structures (laminin, fibronectin, collagen III, collagen IV), as well as collagen I and the proliferation marker MIB-5, using immunohistologic techniques. Tumors arising in the course of the experiments were included in the histologic and immunohistologic investigations. Results: Irradiated SG tissues showed positively dose-dependent histologic tissue alterations, which following an exposure of 60 Gy were mostly stage 2 according to the Seifert classification. Age and time since irradiation had no significant effect. Also, we found increasing, cell-specific CK/IF expressions and intensified/broadened BM immunoreactions (sometimes with formation of conglomerates) with increasing dose. The proliferation marker MIB-5 showed increased expression, most markedly 6 months after completion of irradiation. In irradiated laryngotracheal tissues, slight to moderate non-latency- and non-age-dependent morphologic alterations (dilatations of lymph and blood vessels, edema, interstitial cell infiltrations, fibrosis, supraglottic pseudo-papillary formations, SG atrophy) were detected. These alterations differed with the dose. The CK/IF and BM expression showed only slight to moderate dose-dependent alterations in staining, but demonstrated remarkable heterogeneity, with increases, decreases, and fluctuations in staining. Age and time since irradiation mostly had no significant effect. The intracranial tumors were pituitary adenomas, predominantly of the hormone-producing type. The extracranial malignant tumors of irradiated animals were conspicuous for their histology (carcinomas) and site of origin (mammary crest, SG, maxilla). The benign tumors were spontaneously arising fibromas and fibroadenomas. Conclusions: Using a clinically relevant RT protocol it is possible to avoid maximal irradiation damage of the SG. The predominant lack of dependence on time since irradiation points to persistence of radiation effects. Laryngotracheal tissues showed relative resistance to radiation damage. The altered CK/IF and BM expressions may go some way to explain the morphologic/structural (e.g., frequent laryngeal edema) and functional (e.g., voice disorders) changes associated with head and neck irradiation. Not only sarcomas, but also both carcinomas and hormone-producing pituitary adenomas should be considered in the follow-up of patients irradiated in the head and neck area.