Background: Pediatric-onset SLE (pSLE) is a multisystem autoimmune disease. Recently, the ficolin-2 (FCN2) gene has emerged as a potential candidate gene for susceptibility to SLE. Objectives: The objective of this study was to evaluate the association of the FCN2 gene polymorphisms at positions 986 (G/A), 602 (G/A), 4 (A/G) and SNP C/T (rs3124954) located in intron 1, with susceptibility to pSLE in Egyptian children and adolescents. Methods: This was a multicenter study of 280 patients diagnosed with pSLE, and 280 well-matched healthy controls. The FCN2 promoter polymorphisms at –986 G/A (rs3124952), 602 G/A (rs3124953), 4 A/G (rs17514136) and SNP C/T (rs3124954) located in intron 1 were genotyped by polymerase chain reaction, while serum ficolin-2 levels were assessed using enzyme-linked immunosorbent assay. Results: The frequencies of the FCN2 GG genotype and G allele at 986 and 602 positions were significantly more represented in patients with pSLE than in controls (p < 0.001). Conversely, the FCN2 AA genotype and A allele at position 4 were more common in patients than in controls (p < 0.001). Moreover, patients carrying the FCN2 GG genotype in 986 position were more likely to develop lupus nephritis (odds ratio: 2.6 (95% confidence interval: 1.4–4.78); p ¼ 0.006). The FCN2 AA genotype at position 4 was also identified as a possible risk factor for lupus nephritis (odds ratio: 3.12 (95% confidence interval: 1.25–7.84); p ¼ 0.024). Conclusion: The FCN2 promoter polymorphisms may contribute to susceptibility to pSLE in Egyptian children and adolescents. Moreover, the FCN2 GG genotype at position 986 and AA genotype at position 4 were associated with low serum ficolin-2 levels and may constitute risk factors for lupus nephritis in pSLE.