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The objective of this study was to evaluate and compare the associations between TAS2R16 serum levels and common gene rs860170, rs978739, and rs1357949 polymorphisms in patients affected by generalized periodontitis. The study enrolled 590 patients: 280 patients with periodontitis and 310 healthy controls as a reference group. Patients underwent periodontal examination and radiographic analysis to confirm the periodontitis diagnosis. Blood samples were collected, and the DNA salting-out method was used for DNA extraction from peripheral venous blood. Genotyping of <i>TAS2R16</i> (rs860170, rs978739, and rs1357949) was performed using real-time polymerase chain reaction (RT-PCR), and serum level analysis was performed for both periodontitis-affected patients and reference group subjects. The analysis of <i>TAS2R16</i> rs860170 (TT, CT, and CC) showed a statistically significant difference between generalized periodontitis and the reference group (41.8%, 58.2%, and 0% vs. 38.7%, 56.1%, and 5.2%, <i>p</i> < 0.001). <i>TAS2R16</i> rs860170 (TT, CT, and CC) showed a statistically significant difference between males in generalized periodontitis and reference groups (38.4%, 61.6%, and 0% vs. 32.9%, 56.6%, and 10.5%, <i>p</i> = 0.002). Female-specific analysis showed that the <i>TAS2R16</i> rs978739 C allele was more frequent in generalized periodontitis compared to the reference group (37.5% vs. 28.7%, <i>p</i> = 0.016). Subjects aged 70 years and older demonstrated a statistically significant difference in <i>TAS2R16</i> rs860170 (TT, CT, and CC) between generalized periodontitis and the reference group (42.8%, 57.2%, and 0% vs. 38.6%, 53.8%, and 7.6%, <i>p</i> = 0.003). TAS2R16 serum levels were elevated in generalized periodontitis compared to the reference group (0.112 (0.06) ng/mL vs. 0.075 (0.03) ng/mL, <i>p</i> = 0.002). Females carrying the <i>TAS2R16</i> rs978739 C allele were more prone to generalized periodontitis development. Associations were found between <i>TAS2R16</i> rs860170 polymorphisms, elevated TAS2R16 serum levels, and generalized periodontitis development.