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Objective This study aimed to investigate the clinical significance of serum S100 calcium-binding protein A12 (S100A12) concentrations in patients with community-acquired pneumonia (CAP). Methods This was a case–control study. We selected 120 patients with CAP treated in Xichang People’s Hospital from January to June 2022 as the case group. Sixty healthy adults without a history of basic diseases were selected as the control group. The patients in the case group were divided into the low S100A12 and high S100A12 subgroups. Serum S100A12, C-reactive protein (CRP), and procalcitonin (PCT) concentrations, the leukocyte count, and other study parameters were compared. Results Serum S100A12, CRP, and PCT concentrations and the leukocyte count were higher in the case group than in the control group. The baseline confusion, urea, respiratory rate, blood pressure, and age ≥ 65 score, baseline pneumonia severity index score, and 30-day mortality rate were higher in the high S100A12 subgroup than in the low S100A12 subgroup. Serum CRP and PCT concentrations and the leukocyte count were higher in the high S100A12 subgroup than in the low S100A12 subgroup. Conclusion Patients with high serum S100A12 concentrations have more severe CAP, a more serious inflammatory reaction, and higher 30-day mortality.