Background and Objectives: The aim of this study was to examine how the status of the oral cavity, composition and properties of saliva change in oncological patients with and without Medication-Related Osteonecrosis of the Jaw (MRONJ) undergoing bisphosphonate therapy.Materials and Methods: A retrospective case–control study of 49 oncological patients using bisphosphonates (BPs) was conducted. The study population was divided into two groups—Group I consisted of 29 patients with MRONJ and Group II of 20 patients without MRONJ. The control group consisted of 32 persons without oncological history and without antiresorptive therapy. Standard dental examination included the assessment of the number of teeth remaining, teeth with caries and fillings, Approximal Plaque Index (API) and Bleeding on Probing (BOP). In terms of MRONJ, localization and stage were assessed. Laboratory tests of saliva included determination of pH and concentrations of Ca and PO4ions, total protein, lactoferrin, lysozyme, sIgA, IgA, cortisol, neopterin, activity of amylase at rest, and stimulated saliva. The buffering capacity and microbiological tests (Streptococcus mutans, Lactobacillusspp. load) of stimulated saliva were also determined.Results: There were no statistically significant differences between the selected oral parameters and saliva of Group I and Group II. Significant differences were found between Group I and the control group. BOP, lysozyme and cortisol concentration were higher, while the number of teeth with fillings, Ca and neopterin concentrations were lower in comparison to the control group. In Group I, a significantly higher percentage of patients with a high colony count (>105) ofStreptococcus mutansandLactobacillusspp. was also found. The significant differences between Group II and the control group concerned the concentrations of lysozyme, Ca ions, sIgA, neopterin and the colony count ofLactobacillusspp. In the Group I patients who received a significantly higher cumulative dose of BP compared to the Group II, a significant positive correlation was found between the received BP dose and the BOP. Most MRONJ foci were stage 2 and were mainly located in the mandible.Conclusions: Among oncological patients with and without MRONJ undergoing BP therapy compared to the control group, there are statistically significant differences in the dental, periodontal and microbiological status and in the composition of the saliva. Particularly noteworthy are the statistically significant differences in the decreased level of Ca ions, the increased level of cortisol and the elements of saliva related to the immune response (lysozyme, sIgA, neopterin). Additionally, a higher cumulative dose of BPs may affect the susceptibility to the development of osteonecrosis of the jaws. Patients undergoing antiresorptive therapy should receive multidisciplinary medical care, including dental care.