Mass vaccination against the 2009 A/H1N1 influenza virus, with different vaccine formulations, is being implemented globally. Because of the urgency with which the vaccine has been prepared, little information has been gathered on variables that influence the effectiveness of the vaccine. Specifically, it is not clear whether priming by previous infection with or vaccination against seasonal influenza affects the response to the vaccine. Similarly, the role of vaccine adjuvants in vaccine response is not known. To address these questions, we injected ferrets with seasonal influenza vaccine and then vaccinated with 2009 A/H1N1 vaccine with or without the oil-in-water adjuvant MF59. The results show that the seasonal flu vaccine, although it did not induce functional antibodies against the 2009 A/H1N1 virus, provided immunological priming and allowed production of protective antibodies to 2009 A/H1N1 after one dose of 2009 A/H1N1 vaccine. The vaccine given without adjuvant significantly reduced viral load in the lungs but did not protect from infection. Only the vaccine with adjuvant completely prevented both pulmonary and nasal infection.