Purpose: Salivary biomarkers can present variation in the onset, progression, or even regression of a particular disorder. One such biomarker present in the oral cavity is salivary lysozyme which plays a significant role in the defense mechanism of our body. The purpose of this study was to determine the changes in the levels of salivary lysozyme before and after removable prosthetic treatment in partially edentulous patients. Materials and methods: A total of 40 subjects were enrolled for the study who had reported to the Department of Prosthodontics for a removable partial denture (RPD) of their partial edentulism. A simplified oral hygiene index (OHI-S) was recorded for each subject. The saliva samples were collected at different time intervals, that is, baseline before the removable prosthodontic treatment and 3 months after treatment. This was followed by a comparative analysis of changes in the levels of salivary lysozyme using enzyme-linked immunosorbent assay (ELISA). Categorical variables (like gender) were summarized as frequencies, while continuous variables were summarized as mean and standard deviation. Parametric tests of significance (paired t-test) were used for inferential statistics. Continuous data were tested by means of the Shapiro–Wilk test. Results: The mean value for the OHI-S before removable prosthodontic treatment was 2.41; however, after insertion of the RPD, the value was 3.04 suggesting a significant increase of 0.6225 (p < 0.001). The levels of salivary lysozyme increased essentially in patients after wearing an RPD for 3 months. The initial values were 11.27 ± 0.37, which elevated to 13.10 ± 0.39 in a span of 3 months. Conclusion: The inference of this study advocated that the salivary lysozyme levels may be of significance for the determination of susceptibility to the disease, its progression, or regression pre- and posttreatment following initial colonization of bacteria after the RPD insertion.