Combination vaccines consisting of multiple vaccine antigens delivered in a single injection simplify vaccine administration. Combining multiple antigens into one injection, however, presupposes that the administration of multiple vaccines in combination will not reduce the safety and immunogenicity of the component vaccines. New generation vaccines seek to combine many more antigens from multiple, different pathogens, making them difficult to study in controlled, double blind, randomized clinical trials because of the number of study arms required for complete evaluation. Methods to simplify studies of combination vaccines include building on the framework of earlier studies to calculate sample size and reduce the number of control arms, standardizing serologic assays and assessment of adverse reactions and determining serologic correlates of protection to minimize the need for multiple efficacy studies and to facilitate evaluation of immunogenicity studies. Preliminary data indicate that immune responses to combination vaccines including diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus are comparable with those seen when the vaccines are administered separately. In contrast studies of combination vaccines that include Haemophilus influenzae type b Hib antigens show a diminished Hib antibody response, although the clinical relevance of this lowered antibody response has not yet been determined. Numerous small safety studies of combined vaccines have not found evidence of increased adverse reactions.