Partial sequences of group A streptococcal M proteins exhibit up to 50% sequence identity with segments of rabbit skeletal tropomyosin. It is well recognized that rheumatic fever and rheumatic heart disease in humans are sequelae of group A streptococcal infection. To examine whether the human cardiac tropomyosin would exhibit greater homology with the streptococcal M proteins, we have now determined its complete amino acid sequence. The amino acid sequence of human cardiac tropomyosin was established from sequence analyses of its peptides derived by enzymic and chemical cleavages, and comparison of these sequences to the reported sequence of rabbit skeletal tropomyosin. These studies have revealed that the amino acid sequence of human cardiac alpha tropomyosin is identical to that of the rabbit skeletal alpha tropomyosin, but for a single conservative substitution of Arg/Lys at position 220. This observation increases the significance of the previously observed sequence homology between streptococcal M protein and rabbit skeletal tropomyosin and may have relevance to the pathogenesis of rheumatic fever. Furthermore, these results rank tropomyosin as one of the most highly conserved contractile proteins between vertebrate species reported thus far.