Objective: The aim of this study was to characterize childhood-onset systemic lupus erythematosus (SLE) in two large cohorts from Turkey and the United States. Methods: Patients diagnosed with childhood-onset SLE who fulfilled the 1997 American College of Rheumatology classification criteria for SLE from four reference centers in Turkey and the University of Pittsburgh School of Medicine in the United States were included in this study. A comparative analysis was conducted to evaluate the similarities and differences in clinical and laboratory features, damage accrual, and treatment experiences between the two populations. Results: A total of 174 patients with childhood-onset SLE were included in this study (108 patients from Turkey and 66 patients from the United States). The female-to-male ratio was similar between the two cohorts (∼3:1, p =.73). The median age at diagnosis was 11.67 years (2.19-17.93) in the Turkish cohort and 13.68 years (2.74-17.93) in the U.S. cohort (p <.001). Photosensitivity (45.4% and 21.2%; p =.007) and renal involvement (41.7% and 36.4%; p =.045) were higher in the Turkish cohort. Anti-Ro/SSA (34.8% and 15.7%; p <.001), anti-Sm (59.1% and 19.4%; p <.001), and anti-RNP (47.0% and 14.8%; p <.001) positivity was more frequent in the U.S. cohort. Current use of rituximab (37.9% and 1.9%; p <.001) and belimumab (19.7% and 0%; p <.001) was more prevalent in the U.S. cohort, while the use of cyclophosphamide (often according to the low dose Euro-Lupus protocol) throughout the disease course (24.1% and 4.5%; p <.001) was more frequent in the Turkish cohort. SLICC/ACR Damage Index scores were not different between the two cohorts. Conclusion: This study provides detailed clinical and laboratory features of childhood-onset SLE in two independent and geographically divergent cohorts. Our findings suggest an earlier age of disease onset and a higher prevalence of kidney involvement in Turkish patients. Differences in treatment approaches were also noted. However, damage accrual related to SLE does not appear to be different between the two patient populations.