This study was performed to determine anti-C1q serum level, genetic polymorphism in cytotoxic T lymphocyte–associated antigen 4 gene (CTLA-4 gene) (rs 231775), and HLA class II genes in susceptibility and early prediction of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Upper Egyptian patients. A total of 60 unrelated cases of SLE (30 cases with LN) and 60 healthy controls were studied for HLA-DQB1, HLA-DQA1, and HLA-DRB1 (DR4 subtypes) alleles. Anti-C1q level was estimated by ELISA. CTLA-4 gene genotypes were detected by PCR-RFLP. The means of age of SLE patients without nephritis and LN patients were 24 ± 5.09 and 32 ± 7.26, respectively. Most of the patients were females (93.3%). Anti-C1q serum level was significantly higher in LN patients (24.11 ± 4.26) versus SLE patients without nephritis (18.17 ± 1.35) (p value < 0.001). The AA genotype of the CTLA-4 gene was significantly higher in patients with LN versus SLE patients without nephritis (53.5% vs. 26.5%; p value = 0.035). (DR7)—DQA1*02-DQB1*0303 haplotype was higher in SLE patients versus the control group and showed the highest odds ratio (7.37) with a significant p value (0.031). Odds ratios of DRB1*0405–DQA1*03–DQB1*0302 and DRB1*0405–DQA1*03–DQB1*02 were 6.263 and 4.214, respectively. DRB1*0405–DQA1*03–DQB1*02 haplotype was detected in 11.7% of LN patients versus 1.7% of SLE patients without nephritis (OR = 8.82, p value = 0.02). DRB1*0405–DQA1*03–DQB1*02 haplotype, in addition to CTLA-4 gene (AA genotype), and high anti-C1q serum level can predict the progression of SLE Upper Egyptian patients to LN.