The effects of fractionated X-irradiation following isoproterenol (IPN) administration on rat parotid gland were studied 4, 8, and 12 weeks post-irradiation. Degenerative and necrotic changes of the acinar cells were observed at all three time intervals as a result of the radiation. These changes were more obvious 4 and 8 weeks post-irradiation and isoproterenol administration. The necrotic acinar cells were replaced by fibrous connective tissue, especially conspicuous at 12 weeks. Reparative changes were observed along with the degenerative and regressive phenomena of the gland. Enlarged acinar cells and nuclei were observed as early as 4 weeks post-irradiation. This change was focally distributed at the 4-week interval but more widespread 8 and 12 weeks post-irradiation. Mitochondrial hyperplasia with alteration of mitochondrial cristae was observed 12 weeks post-irradiation. Proliferation of cells of ductal origin and nodular proliferation of ducts were observed 12 weeks after isoproterenol administration plus X-irradiation. These proliferative phenomena may represent an early stage of tumor formation resulting from the combined effect of isoproterenol and X-irradiation on rat parotid gland.