Cells of the immune system are endowed with an array of surface receptors that recognize pathogen-associated molecular patterns. CD14, is a glycosylphosphatidylinositol-anchored, membrane-associated protein that is essential for the recognition of LPS. More recently, CD14 has also been implicated in the recognition of CpG DNA. However, CD14 is not the only receptor that has been shown to bind CpG DNA. We have shown that DEC-205, a multimeric C-type lectin, also bound CpG DNA and played an important role in TLR9-dependent immune activation. DEC-205 and CD14 have a complementary but overlapping expression profile: CD14 is expressed on macrophages, whilst DEC-205 is not. Conversely, DEC-205 is expressed at high levels on CD8+ DC, whilst CD14 is only expressed at low levels on these and other DC subsets. This suggests DEC-205 and CD14 play complementary roles in an intricate cellular system designed to detect CpG DNA. With this in mind, we asked whether mice that lacked both CD14 and DEC-205 were less responsive to CpG DNA. We compared serum cytokines and DC activation in DEC-205-deficient, CD14-deficient and double knock-out mice. Whilst DEC-205-/- mice were clearly impaired in their response to CpG DNA, CD14-/- mice responded normally. Furthermore, double knock-out mice did not display defects beyond those already seen in DEC-205-/- mice. Our data argues that CD14 plays, at best, only a minor role in recognizing CpG DNA, and this minor role may only become apparent in specific experimental condition.