Ginseng replant disease involves the high mortality of ginseng plants (Panax quinquefolius) growing in fields previously used for ginseng cultivation, and is linked to root rot caused by Ilyonectria mors-panacis. One hypothesis for replant disease is that there is a selection for highly virulent isolates in the first crop, but no significant differences in root lesion size were observed among 12 isolates of I. mors-panacis and four isolates of Ilyonectria robusta obtained from diseased roots of ginseng in replant or non-replant soil. However, the average growth rate on potato dextrose agar for I. robusta isolates was greater than for I. mors-panacis, and the average virulence was greater for isolates with greater hyphal pigmentation in culture. Based on nucleotide sequences of all exons of the genomes, the I. robusta isolates were distinguishable from the I. mors-panacis isolates, which were divided into types 1 and 2. The division of I. mors-panacis into types was not related to virulence but to secretome sequence differences, particularly small secreted cysteine-rich proteins and secreted lipases. Treatment of ginseng roots with replant soil extract, but not ginseng root extract or non-replant soil extract, increased lesion sizes of roots inoculated with I. mors-panacis compared to water. Increased lesion size was related to a reduced response to I. mors-panacis infection in expression of five genes related to jasmonic acid (JA), ethylene (ET) or necrotrophic infection, whereas expression of a salicylic acid (SA) related gene was increased. Formation of JA/ET related immunosuppressing compounds in replant soil may be due to soil bacterial activity as ginseng root extracts could be converted into unknown immunosuppressing compound(s) when incubated in culture medium with an isolate of Pseudomonas plecoglossicida obtained from replant soil. Higher growth of the bacterium with ginseng root extract compared to medium alone indicated that root extract acted as a nutrient. It is hypothesized that ginsenosides and/or other ginseng root compounds enter soil where they are microbially converted into immunosuppressing compounds against the JA/ET defense response of ginseng to I. mors-panacis infection following uptake by roots. Prolonged immunosuppression could increase levels of root rot contributing to ginseng replant disease.