The goal of this work is to determine whether the cotton rat, which is highly susceptible to infection with many viruses, can be infected with the human immunodeficiency virus (HIV-1). Two inbred species of cotton rats, Sigmodon hispidus and S. fulviventor, were employed. The LAI laboratory-adapted strain of HIV-1 was used, and both species were infected as determined using PCR and antibody assays. The S. fulviventor strain of cotton rats, however, proved to be the more susceptible. Although virus could not be isolated in cultures of CEM human cells, it was possible to effect two serial transmissions of the virus to other cotton rats. Experiments have been recently initiated using a freshly isolated virus, and these animals were infected early and appear to be carrying significantly more virus in their PBMCs.