Phylogenetic analyses of the families of mammalian lung surfactant proteins (SP-A, SP-B, SP-C, and SP-D) supported the hypothesis that these proteins have diverged between birds and mammals as a result of lineage-specific gene duplications and deletions. Homologs of mammalian genes encoding SP-B, SP-C, and SP-D appear to have been deleted in chickens, whereas there was evidence of avian-specific duplications of the genes encoding SP-A and presaposin. Analysis of the genes closely linked to human SP-B, SP-C, and SP-D genes revealed that all three of these genes are closely linked to genes having orthologs on chicken chromosome 6 and also to genes lacking chicken orthologs. These relationships suggest that all of the lung surfactant protein genes, as well as certain related genes, may have been linked in the ancestor of humans and chickens. Further, they imply that the loss of surfactant protein genes in the avian lineages formed part of major genomic rearrangement events that involved the loss of other genes as well.