Introduction: The palatine tonsils are secondary lymphoid organs where immune processes occur, influencing the development of a targeted cellular and humoral response. The diseased tonsils are subject to immunological imbalances, including the activity of pro-inflammatory and anti-inflammatory factors. This leads to the development of palatine tonsil diseases, such as palatine tonsillitis and palatine tonsillar hypertrophy. Aim: The main aim of the study was to evaluate the similarities and differences in the clinical and pathomorphological pictures of patients qualified for surgical treatment due to hypertrophy or inflammation of the palatine tonsils. The aim was achieved by demonstrating the relationship between the patient’s medical history and physical examination and histopathological diagnosis of a given tonsillar disease, evaluating the usefulness of basic blood tests (leukocytosis, ASO, ESR, and CRP) in differential diagnosis, and assessing the immunohistochemical assessment of palatine tonsil tissue. Material and Methods: The tonsils were stained with the following antibodies: IL-1, IL-2, IL-6, IL-8 IL-10, and IL-37 and CD25, CD40, and CD69, taking into account the histological division of the studied lymphatic tissue (epithelial, subepithelial, follicular, follicular center, and interfollicular). Patients aged between 19 and 70 years with tonsillitis or clinical signs of tonsillar hypertrophy were qualified for tonsillectomy/UPPP. Seventy-two males (68.6%) and thirty-three females (31.4%) were enrolled in the study. Histopathological and immunohistochemical assessment was performed on 105 palatine tonsils. Results: The diagnostic value of blood tests, including determination of ASO, ESR, CRP, and leukocyte level, proved to be a significant predictor of tonsil disease. In the pathomorphological assessment, 75% of the subjects who had simultaneously elevated ESR (>4.73) and leukocytosis (>6.96) and reduced ASO (<161.03) and CRP (<0.31) belonged to the tonsillitis group. The immunohistochemical assessment revealed a diverse profile of the markers tested depending on the diagnosed disease of the tonsils. The follicular center proved to be the region of palatine tonsil tissue for which the most statistically significant differences between the markers were found. Responses to CD-40 and IL-1 were observed in this region. The tissue of epithelial, follicular, and interfollicular regions each showed one statistically significant value for the studied chemokines and lymphokines. However, the lack of significant statistical differences forp< 0.05 between the study groups was only noted in the subepithelial region. It should be emphasized that for the data as a whole (calculated on the basis of the data for all regions together), no statistically significant differences were observed. Conclusion: In conclusion, the results obtained are indicative of the presence of a specific immunohistochemical profile for palatine tonsil diseases. Significant discrepancies have been found in the clinical and pathomorphological assessment of tonsils qualified for tonsillectomy. Therefore, these methods should be considered complementary. The patient’s medical history and physical examination, depending on the adopted clinical or histopathological classification, show a variation in the distribution of features that are the basis for allocation to a particular group.