Background This study aimed to compare the incidence characteristics of peripheral and central-site osteosarcoma (OS) and to explore the impact of different primary sites on the prognosis of patients with OS. Methods Patients diagnosed with OS (1975-2019) were selected from the SEER databases. The different primary sites, diagnosis time and incidence of OS were described statistically. A 1:1 propensity score matching (PSM) was used to adjust for clinical characteristics and treatment. Kaplan-Meier curves were used to compare overall survival and CSS of peripheral and central-site OS before and after matching. Univariate and multivariate Cox models were used to investigate prognostic factors for CSS in both groups. Results A total of 3,129 patients were included (899/28.73% central-site OS, 2166/69.22% peripheral-site OS, 64/2.05% other-site OS) . After PSM, central-site OS had lower overall survival and CSS than peripheral-site OS (5-year overall survival, 0.415 vs. 0.468; 5-year CSS, 0.454 vs. 0.555). Multivariate analysis revealed that age (P=0.010), primary site (P=0.039), historical SEER stage (regional, P=0.012; distant, P＜0.001), histologic grade (grade Ⅲ, P=0.014; grade Ⅳ, P=0.009), surgery (P＜0.001), and radiotherapy (P=0.005) were significant factors for CSS. Subgroup analyses adjusting for these factors showed better CSS in peripheral-site OS patients. Conclusions The incidence of central-site OS is lower than that of peripheral-site OS, while the prognosis of patients with peripheral-site OS is more favorable than that of patients with central-site OS. Surgical intervention is a cornerstone in the management of OS and is effective for both central-site and peripheral-site OS.