The development of vaccines for infectious diseases for which we currently have none, including HIV, will likely require the use of adjuvants that strongly promote germinal center responses and somatic hypermutation to produce broadly neutralizing antibodies. Here we compared the outcome of immunization with the T‐cell dependent antigen, NP‐conjugated to chicken gamma globulin (NP‐CGG) adjuvanted with the toll‐like receptor 9 (TLR9) ligands, CpG‐A or CpG‐B, alone or conjugated with the cationic lipid carrier, DOTAP. We provide evidence that only NP‐CGG adjuvanted with DOTAP‐CpG‐B was an effective vaccine in mice resulting in robust germinal center responses, isotype switching and high affinity NP‐specific antibodies. The effectiveness of DOTAP‐CpG‐B as an adjuvant was dependent on the expression of the TLR9 signaling adaptor MyD88 in immunized mice. These results indicate DOTAP‐CpG‐B but not DOTAP‐CpG‐A is an effective adjuvant for T cell‐dependent protein antigen‐based vaccines.