We develop a model for speciation due to postzygotic incompatibility generated by autoimmune reactions. The model is based on frequency-dependent interactions between host plants and their pathogens, which can generate disruptive selection and give rise to speciation if distant phenotypes become reproductively isolated. Based on recent experimental evidence from Arabidopsis, we assume that at the molecular level, incompatibility between host strains is caused by epistatic interactions between two proteins in the plant immune system—the guard and the guardee. Within each plant strain, immune reactions occur when the guardee protein is modified by a pathogen effector, and the guard subsequently binds to the guardee, thus precipitating an immune response. When guard and guardee proteins come from phenotypically distant parents, a hybrid's immune system can be triggered by erroneous interactions between these proteins even in the absence of pathogen attack, leading to severe autoimmune reactions in hybrids. This generates a Dobzhnasky—Muller incompatibility due to immune reactions. Our model shows how phenotypic variation generated by frequency-dependent host—pathogen interactions can lead to such postzygotic incompatibilities between extremal types, and hence to speciation.