Transmissible gastroenteritis coronavirus (TGEV) infects both, the enteric and the respiratory tract of swine. S protein, that is recognized by the cellular receptor, has been proposed that plays an essential role in controlling the dominant tropism. The genetic relationship of S gene from different enteric strains and non-enteropathogenic porcine respiratory coronaviruses (PRCVs) was determined. A correlation between tropism and the genetic structure of the S gene was established. PRCVs, derived from enteric isolates have a large deletion at the N-terminus of the S protein. Interestingly, two respiratory isolates, attenuated Purdue type virus (PTV-ATT) and Toyama (TOY56) have a full-length S gene. PTV-ATT has two specific amino acid differences with the S protein of the enteric viruses. One is located around position 219, within the deleted area, suggesting that alterations around this amino acid may result in the loss of enteric tropism. To study the role of different genes in tropism, a cluster of viruses closely related to PUR46 strain was analyzed. All of them have been originated by accumulating point mutations from a common, virulent isolate which infected the enteric tract. During their evolution these viruses have lost, virulence first, and then, enteric tropism. Sequencing analysis proved that enteric tropism could be lost without changes in ORFs 3a, 3b, 4, 6, and 7, and in 3'-end untranslated regions (3'-UTR). To study the role of the S protein in tropism recombinants were obtained between an enteric and a respiratory virus of this cluster. Analysis of the recombinants supported the hypothesis on the role in tropism of S protein domain around position 219.