Decay-accelerating factor (DAF; CD55) is a membrane protein that regulates complement pathway activity at the level of C3. To test the hypothesis that DAF plays an essential role in limiting complement activation in the arterial wall and protecting from atherosclerosis, we crossed DAF gene targeted mice (daf-1(-/-)) with low-density lipoprotein-receptor deficient mice (Ldlr(-/-)). Daf-1(-/-)Ldlr(-/-) mice had more extensive en face Sudan IV staining of the thoracoabdominal aorta than Ldlr(-/-) mice, both following a 12-week period of low-fat diet or a high-fat diet. Aortic root lesions in daf-1(-/-)Ldlr(-/-) mice on a low-fat diet showed increased size and complexity. DAF deficiency increased deposition of C3d and C5b-9, indicating the importance of DAF for downstream complement regulation in the arterial wall. The acceleration of lesion development in the absence of DAF provides confirmation of the proinflammatory and proatherosclerotic potential of complement activation in the Ldlr(-/-) mouse model. Because upstream complement activation is potentially protective, this study underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement.