Cross protection is the ability of one virus to prevent or delay infection by a related challenge virus. To examine this phenomena, a potato X potexvirus (PVX) vector (Chapman et al., 1992, Plant J. 2, 549) was used to systemically express the tobacco mosaic tobamovirus (TMV) coat protein (CP) open reading frame in Nicotiana benthamiana. PVX constructs induce mild mosaic symptoms in N. benthamiana, whereas TMV infection results in rapid systemic necrosis and plant death. Healthy plants or plants preinfected with the unmodified PVX vector succumbed to necrosis within 1 week of TMV challenge inoculation. However, plants preinfected with PVX vectors expressing the TMV CP or RNA coding sequence displayed a 1- to 2-week delay in the appearance of TMV-induced necrosis along with reduced accumulations of TMV. Symptom delay and reductions in the accumulation of TMV were more pronounced in plants protected with the vector expressing the TMV CP than with the vector expressing a nontranslatable CP sequence. Protection was overcome more quickly using a 10-fold higher concentration of challenge inoculum and was ineffective against TMV RNA or a TMV construct expressing a distantly related tobamovirus CP. These findings demonstrate that both RNA and protein are involved in this cross protection phenomenon, but that CP is the main contributor to protection. Taken together, these studies indicate that virus vectors can be used to simulate both cross protection and transgene-derived coat protein-mediated protection, thus providing a new method to further investigate the mechanisms behind each.