As the central component of the complement system, C3 has sensory and effector functions bridging innate and adaptive immunity. It is plausible that common genetic variation at C3 determines either serum C3 level or susceptibility to systemic lupus erythematosus (SLE), but only a single, Japanese, study has currently showed genetic association. In a cohort of 1371 individuals from 393 UK white European SLE families, we quantified serum C3 and genotyped C3 tagSNPs. Using a Bayesian variance components model, we estimated 39.6% serum C3 heritability. Genotype/serum C3 association was determined by mixed linear models. Single nucleotide polymorphism (SNP) rs344555, located in a haplotype block incorporating the 3' end of C3, was associated with serum C3 (P=0.007), with weaker associations observed for other SNPs in this block. In an extended cohort of 585 SLE families the association between C3 variants and SLE was assessed by transmission disequilibrium test. SNP rs3745568 was associated with SLE (P=0.0046), but not with serum C3. Our disease associated SNP differs from that highlighted in the Japanese study; however, we replicate their finding that genetic variants at the 3' end of C3 are associated with serum C3. Larger studies and further fine mapping will be required to definitively identify functional variants.