After unilateral footpad inoculation with herpes simplex virus (HSV) the infection spreads initially to the ipsilateral and afterwards to the contralateral spinal ganglia. In about 25 percent of the mice the virus also reaches the trigeminal ganglia. Furthermore, we have shown that only a complete severance of the nervous connections can prevent the colonization of ganglia with HSV after footpad inoculation. Results of previous experiments in which only the sectioning of the sciatic nerve was able to prevent the invasion of ganglia, are difficult to explain. It appears also that HSV travels in the nerve toward the ganglia in a non-infectious form, and that the infectious virus detectable in nerves originates not from the peripheral inoculation site, but from the infectious virus pool which accumulates in spinal ganglia. A limited role of the circulatory system in the colonization of sensory ganglia by HSV cannot be excluded, since in a few cases virus was detected in ganglia after sectioning of both the sciatic and the femoral nerve.