Forty older adults with chronic diseases were vaccinated intranasally with either influenza A/California/10/78 (H1N1) (CR37) or influenza A/Washington/897/80 (H3N2) (CR48) virus. No clinically significant morbidity or decrement in pulmonary function occurred postvaccination. Two (15%) recipients of CR37 virus and twelve (44%) recipients of CR48 virus became infected with vaccine virus, as indicated by a fourfold rise in serum hemagglutination inhibition antibody titer; a fourfold rise in serum immunoglobulin G (IgG) or IgA antibody titer, indicated by enzyme-linked immunosorbent assay; isolation of vaccine virus from nasal washings; or all of these. Within 1 year after cold-recombinant vaccine virus vaccination, 18 vaccines received inactivated trivalent influenza virus vaccine parenterally. Of the vaccinees, 13 (72%) developed a fourfold rise in serum antibody titer to H1N1 antigen and 16 (89%) developed a fourfold rise in serum antibody titer to H3N2 antigen. We conclude that administration of these cold-recombinant vaccine viruses to older adults with chronic diseases was safe, but that serum antibody response rates were lower than those achieved with subsequently administered inactivated influenza virus vaccine given parenterally. However, the higher seroconversion rates attained by using the inactivated trivalent influenza virus vaccine do not necessarily mean that it is more efficacious in preventing infection or severe illness or both due to natural wild-type influenza A virus.