Ideally, a candidate pandemic influenza vaccine should elicit rapid and strong cell-mediated and humoral immune responses, which are long-lasting and exhibit broad cross-reactivity against drifted strains. The present study investigated the detailed humoral and cellular immune responses in mice vaccinated intranasally or intramuscularly with inactivated influenza H5N1 (NIBRG-14) virosomal vaccine alone or formulated with Matrix-M adjuvant. The intramuscular Matrix-M-adjuvanted vaccine induced a strong immediate and long-term humoral immune response with high cross-reactivity against drifted H5N1 viruses and showed a dose-sparing potential. Additionally, the vaccine induced a balanced Th1/Th2 cytokine profile and most importantly high frequencies of multifunctional Th1 CD4(+) cells. Our results highlight that Matrix-M adjuvant is a promising parenteral adjuvant for formulating pandemic candidate vaccines.