Abstract Summary The safety and immunogenicity of a new virosome influenza vaccine was compared to commercial whole-virus vaccine and subunit vaccine in elderly people. The virosome vaccine was made by extracting the haemagglutinin from influenza virus and incorporating it into the membrane of liposomes composed of phosphatidylcholine (PC) and phosphatidylethanolamine (PE). 126 residents of a nursing home, aged 63-102, were randomised to receive one of the vaccines. All three were well tolerated and caused a significant rise in the geometric mean anti-haemagglutinin inhibiting (HAI) antibody titre to the 3 vaccine components (H1N1 Singapore, H3N2 Beijing, and B/Yamagata). The virosome formulation caused the highest geometric mean titres in addition to significantly (p=0·039-0·0016) higher rates of more than four-fold or more titre rises to all 3 vaccine components. The percentage of those immunised who achieved protective levels of antibody (HAI ≥40) was significantly (p=0·035-0·0017) higher for the H1N1 and B/Yamagata strains following immunisation with virosome formulation. Participants with non-protective baseline titres to the H1N1 or B/Yamagata strains were more likely (p=0·0049-0·006) to achieve protective levels of antibodies after immunisation with the virosome vaccine. Immunisation with the virosome formulation did not result in a significant rise in anti-PC or anti-PE antibodies.