Pale swallowwort (PSW) and black swallowwort (BSW) are two viney milkweeds native to Europe that have increasingly become problematic and noxious weeds in eastern North America. An indigenous fungal isolate, Sclerotium rolfsii VrNY, was discovered causing significant mortality in a dense stand of PSW in a park in upstate New York. Although this fungus is a known pathogen with a broad host range, we evaluated the host potential of S. rolfsii VrNY on a limited range of related and nonrelated U.S. species as a critical first step to assess its suitability as a mycoherbicide for PSW and BSW. In addition, PSW and BSW produce the specific stereoisomer (−)-antofine, a compound with antimicrobial and phytotoxic activity that could inhibit the pathogen. Tests revealed this compound had no effect on S. rolfsii VrNY. This isolate caused significant mortality on all broadleaf plants tested (Asclepias syriaca, Asclepias curassavica, Apocynum cannabinum, Monarda fistulosa, Rudbeckia hirta, PSW, BSW) with the exception of Glycine max, and had no effect on the monocots Schizachyrium scoparium and Zea mays. Although these laboratory studies indicate that most broadleaf vegetation may be susceptible to the pathogen, S. rolfsii might have potential as a mycoherbicide in natural eco-niche environments where invasive PSW and BSW have already become the predominant vegetation. Further laboratory testing of S. rolfsii and limited field testing at the initial discovery site are needed in order to prevent premature rejection of this isolate as a potential management tool against these highly invasive weeds.