Objective: The aim of this study was to evaluate the relevance of genetic variants of interleukin receptor-associated kinase-M ( IRAK-M) (rs11465955, rs1624395, rs1152888 and rs1370128) and single immunoglobulin IL1-1R-related molecule (SIGIRR) (rs3210908) genes in systemic lupus erythematosus (SLE) in four independent European-descent populations. Methods: Our study population consisted of a total of 2033 SLE patients and 2357 healthy controls from Spain, Germany, Italy and Argentina. The genotyping was performed using a polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. Genetic association between the genotyped markers was determined by PLINK v1.07. Results: After a meta-analysis including these four populations, a trend of association between rs11465955 ( P_{meta-analysis} = 0.06), rs1370128 ( P_{meta-analysis} = 0.07) and rs1624395 ( P_{meta-analysis} = 0.06) polymorphisms was found. However, these differences did not reach statistical significance. In addition, we did not find any association between SLE and the rs1152888 IRAK-M ( P_{meta-analysis} = 0.13) and the rs3210908 SIGIRR ( P_{meta-analysis} = 0.40) polymorphisms after the meta-analysis. No evidence of association with IRAK-M haplotypes was found. Conclusion: These results suggest that the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to SLE in European-descent populations.