Responses to influenza vaccination are poor in frail elderly subjects who suffer the greatest morbidity and mortality due to infection. Therefore, a randomized clinical trial was performed to determine the effect of a double dose and booster vaccination on antibody responses after influenza vaccination. A total of 815 patients (median age 83 years, median disability score 8, median disease categories 2 and median number of medications 4) residing in 14 nursing homes in the Netherlands were vaccinated during the influenza season 1997-98. The first vaccine dose (15 or 30 microg) was given on Day 0 followed by a booster dose (placebo or 15 microg) on Day 84. Blood samples were taken before and 25 days after vaccination. There were four treatment groups: (i) 15 microg and placebo, (ii) 15 microg and 15 microg booster, (iii) 30 microg and placebo and (iv) 30 microg and 15 microg booster. Geometric mean antibody titers of those receiving the double vaccine dose was 15% (95% CI, 6% to 24%, P = 0.001) higher as compared to the standard 15 microg dose. A booster dose, given 84 days after the first vaccination, yielded postvaccination titters that were 14% (95% CI, 9% to 19%, P = 0.001) higher as compared to placebo. Subgroup analysis did not reveal patient groups that had a proportionally greater benefit from adapted vaccination strategies. It is concluded that higher antibody responses can be achieved in frail elderly people by a double vaccine dose or a booster vaccination.