The observations from the present study indicate that vaginal formulations of the sulfated polysaccharide carrageenan are highly effective in protecting mice from herpes simplex virus type 2 (HSV-2) infection. Test formulations were placed in the vaginas of progestin-treated mice prior to inoculation with HSV-2. Infection was determined by the presence of inflammation in the genital region and death. At a dose of virus that infected half of the control animals, 1% solutions of either lambda, kappa, or iota carrageenan prevented infection of almost all of the animals. Concentrations as low as 0.05% protected a large majority of the mice. At a dose of virus that infected all of the control mice, 1% solutions of carrageenans protected 85% of the inoculated mice. Other sulfated polysaccharides were less effective or showed no efficacy in preventing HSV-2 infection. These findings suggest that a vaginal formulation of carrageenan may be effective in blocking sexual transmission of HSV-2 in women.