Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and can affect several organs and systems. It is characterized by high production of autoantibodies against nuclear compounds. TLR7/8/9 are responsible for nucleic acid recognition and they trigger proinflammatory responses through activation of NK-kappaB and Type I IFN production, making a bridge between the innate and the adaptative immune systems. We analyzed the frequency of TLR7 rs179008, TLR8 rs3764880, TLR9 rs5743836 and rs352140 in 370 patients with SLE and 415 healthy controls from southern Brazil. All analyses were conducted with regard to gender and ethnicity. Genotypic and allelic frequencies were different for TLR7 rs179008 (0.253 vs. 0.163, p = 0.020 and p = 0.003, OR for T allele: 1.74 CI 95% 1.12–2.70) and TLR9 rs5743836 (0.174 vs. 0.112, p = 0.045 and p = 0.017, OR for C allele: 1.59, CI 95% 0.99–2.57) between European-derived female groups. A higher frequency was observed for the presence of Anti-SSa/Ro for TRL9 rs5743836 C allele carriers (0.228 vs 0.126, Bonferroni corrected p = 0.06). No statistical differences were found for TLR9 haplotypic analyses. We suggest that TLR7 rs179008 and TLR9 rs5743836 can be considered SLE susceptibility factors for women of European descent in our population.