Both mean genomes size and the variance in genome size among species are smaller on average in birds (class Aves) than in the other tetrapod classes. In order to test whether loss of protein-coding genes has contributed to genome size reduction in birds, we compared the chicken genome and five mammalian genomes. Numbers of members (paralogs) were significantly lower in the chicken gene families than in the corresponding mammalian families. Phylogenetic analyses of chicken, mammal, and fish paralogs supported the hypothesis that chicken-specific loss of paralogs occurred much more frequently than mammal-specific gene duplications. Moreover, the phylogenetic analyses supported the hypothesis that a substantial majority of the paralogs lost in chicken originated from duplications prior to the most recent common ancestor of tetrapods and bony fishes. In addition to loss of paralogs, numerous gene families present in the mammalian genomes were missing in the chicken genome; over 1,000 of these families were found in bony fishes, implying presence of the family in the tetrapod ancestor. In the set of families with more members on average in the mammals than in the chicken, immune system function was associated with a greater degree of gene family size reduction in the chicken, consistent with other evidence that immune system gene families have become particularly compact in birds.