Juvenile-onset systemic lupus erythematosus (jSLE) is an uncommon yet severe autoimmune/inflammatory condition affecting multiple bodily systems, typically manifest-ing before the age of 18. This disease exhibits significant complexity, displaying considerable variation among patients. Its effects can range in severity from minor to fatal, characterized by a pattern of recurring flare-ups and periods of remission, making its natural progression difficult to predict. The aim of this work is to investigate the correlation between semaphorin 3A and systemic lupus erythematosus patients who follow up at Pediatric Rheumatology Unit Chil-dren's Hospital at Cairo University. This cross-sectional research was performed at the Pediatric Rheumatology Unit Cairo University Children's Hospital and included cases with jSLE under treatment and fol-low-up from the period of August 2021 to August 2022. Regarding demographic data of the studied subjects, highly significant variances were noted among the patient group & control group regarding age (years) & sex. However, there were non-significant variances among the patient group and control group concerning weight. In the current research, median (IQR) onset of disease was 2 (1 3) years, mean ± SD age at dis-ease diagnosis was 8.98 ± 2.13 years, median (IQR) disease duration 2 (1 3) years, family history was negative in 36 (90.0%) patients and consanguinity was negative in 28 (70.0%). The distribution of the manifestations within the patients group was as follow 7 (17.5%) with mu-cocutaneous, 7 (17.5%) with vasculitis, 4 (10.0%) with serositis, 11 (27.5%) with cardiac, 17 (42.5%) with renal, 11 (27.5%) with GIT, 5 (12.5%) with hematological, and 4 (10.0%) with neu-rological manifestations. In addition, there were 2 (5.0%) with arthritis, 31 (77.5%) with arthral-gia, and 2 (5.0%) with fever mean ± SD systolic BP was 115.95 ± 8.38 & mean ± SD diastolic BP was 75.60 ± 6.11. Regarding treatments in the patients' group, the median steroid dose was 15mg (5-25) with medi-an duration of 2 (1 3), 38 (95.0%) patients received hydroxychloroquine with mean ± SD hy-droxychloroquine dose of 205.26 mg ± 51.71. 23 (57.5%) patients received cyclophosphamide with mean ± SD number of cyclophosphamide doses 7.17 mg ± 2.42. Mycophenolate was re-ceived in 27 (67.5%) with mean ± SD dose of 614.07 mg ± 225.85. There were highly statistically significant differences between control group and patients' group concerning TLC, creatinine, & ESR. Highly statistically significant variance was noted among the control group and patients group concerning CRP. Regarding the patients' group, the mean ± SD serum C3 was 99.89 mg/dl ± 28.45, median (IQR) serum C4 was 14.5 mg/dl (8.8 25.5), and median (IQR) albumin creatinine ratio was 27 IU/ML (16 186). There was positive ANA with titre and pattern in 34 patients (85.0%), positive antids-DNA in 25 patients (62.5%), and positive anticardiolipin IgM and IgG in 5 patients (12.5%). Renal biopsy was found to be normal in 23 (57.5 percent), lupus nephritis class II, III in 3 (7.5 percent), lupus nephritis class III in 10 (25.0%), and lupus nephritis class IV in 4 (10.0%). Urine analysis results showed the following: normal in 28 (70.0%), albumin in 2 (5.0%), casts in 2 (5.0%), pus cell in 4 (10.0%), albumin + casts in 2 (5.0%) and albumin + pus cell in 2 (5.0%). Regarding semaphorin 3A level, a highly statistically significant variance was noted among the control & patients group concerning semaphorin 3A level found to be lower in cases than control with a p-value below 0.001. In patients' group, a negative correlation for semaphorin 3A with SBP, DBP, AST and ESR and also a positive correlation with steroid duration in the studied pa-tients. In addition, highly significant association between semaphorin 3A & positive CRP. How-ever, no significant relationship between semaphorin 3A & SLE manifestations except arthritis was found related to semaphorin 3A level. ROC curve shows that the semaphorin 3A cut-off point to predict SLE ≤ 3 with sensitivity = 47.50, specificity=92.50, PPV=86.4, and NPV=63.8. Reduced plasma Semaphorin 3A levels were found in this study; furthermore, their clinical relationship in SLE proposes their significant job in this illness. Furthermore, the ROC results demonstrated that Semaphorin 3A could be a new symptomatic biomarker in SLE with very high sensitivity for the determination of SLE, demonstrating that they might be helpful bi-omarkers for the evaluation of SLE. However, extra studies that focus on the potential role of Semaphorin 3A in SLE are needed.