Full-length infectious cDNA clones were constructed for two isolates (LMV-0 and LMV-E) of Lettuce mosaic virus (LMV), a member of the genus Potyvirus. These two isolates differ in pathogenicity in susceptible and tolerant-resistant lettuce cultivars. In susceptible plants, LMV-0 induces mild mosaic symptoms, whereas LMV-E induces severe stunting, leaf deformation, and a necrotic mosaic. In plants carrying either of the two probably allelic recessive resistance genes mo1¹ or mo1², LMV-0 is restricted partially to the inoculated leaves. When a systemic invasion does occur, however, symptoms fail to develop. LMV-E overcomes the protection afforded by the resistance genes, resulting in systemic mosaic symptoms. Analysis of the behavior of recombinants constructed between the two virus isolates determined that the HC-Pro protein of LMV-E causes the severe stunting and necrotic mosaic induced by this isolate in susceptible cultivars. In contrast, the ability to overcome mo1 resistance and induce symptoms in the resistant-tolerant cultivars was mapped to the 3′ half of the LMV-E genome. These results indicate that the ability to induce severe symptoms and to overcome the protection afforded by the recessive genes mo1¹ or mo1² are independent phenomena.