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Mal de Rio Cuarto (MRC) is a devastating disease that reduces yield, quality and economic value of maize in Argentina. The objective of the present study was to map quantitative trait loci (QTL) for reactions to MRC from recombinant inbred lines (RILs). Reactions to the endemic MRC disease were evaluated in 145 advanced F-2:6 lines, derived from a cross between a resistant (BLS14) and a susceptible (Mo17) line, at four environments in the temperate semi-arid crop region of Argentina. The evaluations of disease score (SCO), disease incidence (INC) and disease severity (SEV) were carried out on each individual RIL. Low heritability estimates were found across environments for SCO (0.23), INC (0.27) and SEV (0.22). A genetic map of simple sequence repeat (SSR) markers covering a total genetic distance of 1019 cM was built. QTL for resistance to MRC disease were found on different maize chromosomes. Four significant QTL, each explaining between 0.08 and 0.14 of the total phenotypic variation, were located on chromosomes 1, 4 and 10. Two QTL specific to the INC, and one specific to SEV, may be involved in different mechanisms of resistance to MRC. Although MRC reaction is highly affected by environmental effects, the QTL x environment interaction for INC and SEV was low. Most of the QTL for reaction to MRC detected in the present study were mapped to regions of the maize genome containing genes conferring resistance to various pathogens. The significant QTL across environments are good candidates to select for MRC resistance.