Adjuvants function as an enhancer and activator of the immune response and can be of pivotal importance for the efficacy of vaccines. AS01, which is a liposome formulation spiked with the saponin derivate QS-21 and the detoxified lipopolysaccharide MPL-A, and AS03, which is a squalene-based oil in water emulsion that contains antioxidant tocopherol, are modern, highly potent adjuvants that became integral to innovative vaccines. In the current study, guinea pigs –a well-established small animal model for human influenza-infections– were subcutaneously vaccinated with an influenza H5N1-antigen formulated with AS01, AS03, aluminium hydroxide or left unformulated. The induction of T- and B cells specific for the influenza antigen was assessed in dependence of the antigen formulation. H5N1-specific T cell responses were observed with all adjuvant formulations, but after six months were highest in the AS01- and AS03-immunized groups. The influenza specific antibody titres were highest in AS03-vaccinated guinea pigs. Importantly, AS03- and AS01-formulated influenza antigen also induced crossreactive antibodies inhibiting related H5N3- but not a distant H5N8-influenza strain. At the same time, it was observed that animals, which received the egg-produced H5N1 split antigen in combination with AS03, mounted xenoreactive, opsonizing antibodies that bound to chicken fibroblasts. No reactivity was observed to human fibroblasts. In summary, our results confirm the superior adjuvanticity of AS03 and of AS01 as compared to conventional alum or non-adjuvanted formulations. The presence of xenoreactive antibodies after AS03 vaccination was an unexpected observation. Further investigations will be required to appreciate the significance and identify the mechanisms of this findings.