Dense deposit disease (DDD) is a rare, progressive and incurable kidney disease characterized by complement C3 accumulation along the glomerular basement membrane (GBM). It is the prototypical form of C3 glomerulopathy, which comprises renal disorders due to excessive C3 activation via the alternative pathway (AP). Human and murine studies indicate that renal inflammation in DDD is initiated by the specific C3 activation product iC3b. I have assessed the role of iC3b in DDD using the uniquely informative experimental model of C3 glomerulopathy in factor H (FH)-deficient mice. I demonstrate that coexisting deficiency of CD11b, the specific leukocyte receptor for iC3b, exacerbates the spontaneous renal phenotype in FH-deficient mice. This suggests that the iC3b-CD11b interaction may mediate partial renal protection in DDD. I also show that CD11b deficiency produces hypersensitivity to experimentally triggered glomerular injury in both FH-deficient and FH-sufficient mice. My second experimental approach in vivo and in vitro was to assess whether C3 activation in the circulation or on the GBM surface is the predominant cause of iC3b accumulation in DDD. This included experiments in which administration of a novel engineered human FH protein fragment reduced glomerular C3 staining in FH-deficient mice.