Lupus nephritis (LN) remains one of the most serious manifestations of systemic lupus erythematosus (SLE) associated with considerable morbidity and mortality. This study was planned to test for the association of TNF-α -308 G>A and IFN-γ +874 A>T gene polymorphisms with susceptibility of LN in Egyptian patients. Subjects and Methods: A cross-sectional study was conducted on 125 patients (72 females and 53 males) suffering from SLE having LN. Control group consisted of 112 age matched healthy (46 males and 66 females) individuals. For all patients, characterization of TNF-α -308 G>A and IFN-γ +874 A>T genetic polymorphisms was done using the allele-specific PCR technique. Results Regarding TNF-α -308 G>A, the A allele was associated with a significantly elevated odd ratio (OR) of 3.2 (95% confidence interval (CI) =2.15 -5.01, P = 0.003) in SLE cases associated with LN. The AA genotype, was statistically insignificant (95% CI = 0.61-46.5, P 0.12) increased risk. Combined genotypes (AA plus GA) versus GG was associated with a significant increase in SLE having nephritis compared to controls (OR = 2.51, 95% CI = 1.26-4.99, p=0.009). Regarding the IFN-γ +874, the T allele of this gene was not associated with increased risk of SLE having nephritis (OR 1.43, 95% CI =0.93-2.20, p 0.13). Genotype AT was associated with increased association of SLE having nephritis (OR 2.06, CI= 3.62-1.18, p = 0.01). In Conclusions: Polymorphisms related to TNF-α -308 G>A and IFN-γ +874 A>T genes may be considered as genetic risk factors for SLE having lupus nephritis.