Recent studies have tested genetic variation at the C1QA, C1QB and C1QC (complement component 1, q subcomponent, A chain, complement component 1, q subcomponent, B chain and complement component 1, q subcomponent, c chain) loci in relation to systemic lupus erythematosus (SLE) risk. Evidence for a significant effect of C1Q locus gene polymorphisms on SLE predisposition remains unclear. We aimed to identify associations between common C1Q polymorphisms and SLE risk and serum C1q, C3 and C4 levels. We performed family-based association tests in 295 nuclear families with one affected proband. Tag-single nucleotide polymorphisms (SNPs) ranging from 35.4 kb upstream of the C1QA gene to 28 kb downstream of the C1QB gene were selected to represent the entire C1Q gene locus. We performed transmission disequilibrium tests for affectation status and continuous traits, including C1q, C3 and C4 levels using family-based association tests (FBAT). There was no evidence for a significant role of C1Q locus gene polymorphisms in SLE risk predisposition. The strongest association was observed with a variant in the 3'UTR region of the C1QB gene (rs294223, P = 0.06). We found nominally significant associations with a second variant (rs7549888) in the 3'UTR region of the C1QB gene and C1q (P = 0.01), C3 (P = 0.004) and C4 levels (P = 0.01). In a large family-based association study of C1Q gene cluster polymorphisms no evidence for a genetic role of C1Q locus SNP in SLE risk predisposition was obtained in patients of European ancestry. This is in contrast to other cohorts, in which single variants associated with C1Q, C3 and C4 levels and nephritis have been studied and shown associations.