Background: SLE is an autoimmune disease with complex etiology. Genetic aberrations disrupting the immune regulatory mechanisms may initiate autoimmune disease development. As CTLA-4 is a negative regulator of T-cell immune response and IL-1β is a potential pro-inflammatory cytokine, their allelic polymorphisms might have an impact on SLE susceptibility. Objectives: To investigate a possible association between the polymorphisms of interleukin-1β (IL-1β) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) genes and increased susceptibility and activity of systemic lupus erythematosus (SLE). Methodology: This study was conducted on 50 SLE patients and 25 age- and sex-matched healthy individuals. All patients were subjected to full clinical evaluation and laboratory investigations. The studied groups were genotyped for CTLA-4 -318 C/T and IL-1β -31 T/C polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: The TT genotype and T allele frequencies of the IL-1β -31 T/C polymorphism were significantly (P <0.05) higher in SLE patients than controls. In SLE patients, significant (P <0.05) association of IL-1β -31 T/C polymorphism and SLE activity was observed in TT genotype. There was an increased frequency of TT genotype of IL-1β -31 T/C polymorphism in SLE patients with arthritis and vasculitis compared to those without these manifestations. SLE patients with TT genotype had higher SLEDAI score, anti-dsDNA titer and ESR compared to those with C/T or CC genotypes. On the other hand, the disease susceptibility and activity, demographic characters, clinical data, SLEDAI score, clinical manifestations, autoantibody profile and laboratory characteristics had insignificant association with different genotypes of CTLA-4 -318 C/T polymorphism (P >0.05). Conclusion: IL-1β -31 T/C but not CTLA-4 -318 C/T polymorphisms are associated with increased SLE susceptibility and activity.