Simple Summary Perianal gland tumors are among the most common tumors in sexually intact male dogs. They are hormone-dependent tumors expressing androgen receptors (ARs) and estrogen receptors (ERs). Therefore, the treatment of choice for benign perianal tumors is castration. Surgical treatment is indicated in large benign ulcerated tumors, in malignant tumors, or in cases of recurrence. An alternative method may be pharmacological treatment by administering drugs that block hormone receptors. In the conducted studies, complete tumor regression was obtained in benign tumors and partial regression was obtained in malignant tumors after the administration of tamoxifen and cyproterone acetate, which are pharmacological hormone receptor blockers. The obtained results indicate that pharmacological antihormonal therapy may be considered as an alternative or neoadjuvant therapy for male dogs with perianal tumors. Abstract The presence of androgen (AR) and estrogen (ER) receptors has been demonstrated both in normal perianal (hepatoid) glands and in perianal tumors. The aim of this study was to demonstrate the relationship between the expression of AR and ER in perianal gland tumors and the effectiveness of antihormonal treatment. The study was performed on 41 male dogs with neoplastic lesions of the anal region. Histopathological evaluation of the lesions revealed 24 adenomas, 12 epitheliomas, and five carcinomas. Treatment was administered orally with tamoxifen at a dose of 1 mg/kg BW and cyproterone acetate at a dose of 5 mg/kg. Tumor diameters were measured regularly with calipers and recorded in millimeters starting with the measurement before treatment, and then after 1, 2, 3, 6, 12, 18, and 24 months of therapy. The results show that hepatoid adenomas that are characterized by high expression of AR and ER receptors respond positively to antihormonal therapy, resulting in complete tumor regression. For locally malignant hepatoid epitheliomas and carcinomas with low expression of AR and ER receptors, antihormonal therapy makes it possible to reduce the size of the tumor, but does not make it possible to cure it completely.