Extensive research in the area of plant innate immunity has increased considerably our understanding of the molecular mechanisms associated with resistance controlled by a dominant resistance gene. In contrast, little is known about the molecular basis underlying the resistance conferred by quantitative trait loci (QTLs). In this study, using the interaction of tomato (Solanum lycopersicum) with Oidium neolycopersici, we compared the cytological, biochemical and molecular mechanisms involved in both monogenic and polygenic resistances conferred by a dominant gene (Ol-1) and three QTLs (Ol-qtls), respectively. Our results showed that the three Ol-qtls jointly confer a very high level of broad-spectrum resistance and that the resistance is associated with both the hypersensitive response and papillae formation, with the hypersensitive response being prevalent. Both H2O2 and callose accumulation, which are coupled with Ol-1-mediated resistance, are also associated with the resistance conferred by Ol-qtls. Further, we analysed the pathogen-induced transcript profiles of near-isogenic lines carrying the three Ol-qtls and the Ol-1 gene. Transcript profiles obtained by cDNA-amplified fragment length polymorphism analysis showed that, on fungal challenge, about 70% of the transcript-derived fragments are up-regulated in both susceptible and resistant genotypes. Most of the sequenced transcript-derived fragments showed homology to genes with functions in defence responses, suggesting that defence-responsive genes responsible for basal defence are involved in both monogenic and polygenic resistances conferred by Ol-1 and Ol-qtls, respectively. Although about 18% of the identified transcript-derived fragments are specific for either monogenic or polygenic resistance, their expression patterns need to be further verified by quantitative reverse transcriptase-polymerase chain reaction.