The interaction between Mycoplasma pneumoniae and its natural host, humans, cannot be studied directly for obvious reasons. Therefore, we used guinea pigs instead, which had been recently introduced as an acceptable alternative host organism. The following experimental approaches were taken to study the pathogen-host relationship: characterization and subtyping of M. pneumoniae strains isolated from human patients, infection of guinea pigs with selected M. pneumoniae strains, and analysis of adaptation, preference and survival of individual strains in guinea pigs under competitive conditions. The results of our study indicated that the species M. pneumoniae is genetically very homogeneous. From 115 independently isolated strains two subtypes and one variant were found. The subtypes differed significantly in the amino acid composition of the P1 protein, the main adhesin of M. pneumoniae, while the variant showed only minor amino acid exchanges. Infection of guinea pigs indicated differences between the subtypes and the variant in their ability to colonize and survive in the animal. Preinfection of the host with a certain subtype or variant caused a subtype-specific immunity and had a strong influence on the type of surviving bacteria in superinfection experiments. The results of these studies explain the shift of subtypes frequently observed in epidemic outbreaks of M. pneumoniae infection appearing in intervals of 3-7 years.