Abstract: Objective　This study aims to investigate the drug resistance, resistance mechanisms, and serotype epidemiological features of clinically isolated Streptococcus pneumoniae (SP) in Shanxi Province. Methods　SP strains were isolated between January 2021 and July 2023 from Shanxi Provincial People's Hospital. An automatic microbiological identification and drug sensitivity analysis system was used to identify strains and conduct antibiotic susceptibility assay. The species identification was also carried out using a MALDI-TOF mass spectrometer, optochin assay, and amplification of the CPSA gene. Finally, the polymerase chain reaction (PCR) technique was implemented for drug-resistant and virulence gene detection and serotyping. Results　A total of 117 strains were isolated including 115 strains (98.3%) being erythromycin-resistant Streptococcus pneumoniae (ERSP). The ERSP was composed of 114 macrolide-lincosamide-streptogramin B (MLSB) resistant strains, carrying the ermB (114/114) and mefA (42/114) gene, and one M-resistant strain absent of ermB and tetM. The most common pneumococcal six serotypes in ERSP strains were 19F, 3, 34, 19A, 6A/6B, and 23F, respectively, totaling 71 strains (61.7%). Compared with pediatric and adult, serotype 19F in geriatric patients was the dominant type with a significant difference (χ2=6.315, P=0.043). Compared with adult patients, the strains isolated from pediatric and elderly patients showed a higher rate of insensitivity (resistance and intermediate) to oral penicillin (χ2=7.277, P=0.026). Serotype 19F strains showed high insensitivity to oral penicillin (81.0%), compound sulfamethoxazole (100.0%), tetracycline (94.7%), and ceftriaxone (9.5%). The serotypes 19A and 23F strains also showed high insensitivity to penicillin (>70%), tetracycline (100%) and compound sulfamethoxazole (>85%). However, serotype 3 strains had low insensitivity to oral penicillin (8.3%), ceftriaxone (0%), and compound sulfamethoxazole (27.3%). There were 42 strains positive for ermB+mefA, of which serogroup 19 was the main type, accounting for 64.3% (27/42). Of these strains, 88.1% (37/42) carried ply, lytA, and HylA genes simultaneously. Conclusion　Drug resistance to ERSP still to be a serious problem for human health. There are differences in serotype distribution in terms of age, resistance genes, and drug resistance. Therefore, the vaccination of pneumococcal conjugate vaccine 13 (PCV13) is an essential and effective measure to prevent SP infection in this region.