The efficacy of vaccine adjuvants can be influenced by the immunological environment of the host, depending on the mechanism(s) by which they exert their immunopotentiating activities. Interleukin-6 is a pleiotropic cytokine that has a broad range of biological activities on immune and non-immune cells. We investigated the role of IL-6 on the ability of nine adjuvant formulations to induce antibody responses to the Plasmodium falciparum MSP1-19 malaria vaccine, using IL-6-/- (KO) mice. Results showed that some adjuvants, i.e. MPL-SE, CFA/IFA, ISA720/QS21/MPL, depended on IL-6 for their efficacy, while others exhibited increased potency in its absence. The efficacy of adjuvants in the IL-6 KO environment cannot be solely attributed to their ability to stimulate antigen-specific cellular responses, suggesting that other biological activities of IL-6 are also important. The results further suggest that two adjuvants utilized dissimilar pathways to potentiate the same type of immune response.