In this paper, we determine the genetic architecture controlling leaf flecking in maize and investigate its relationship to disease resistance and the defense response. Flecking is defined as a mild, often environmentally dependent lesion phenotype observed on the leaves of several commonly used maize inbred lines. Anecdotal evidence suggests a link between flecking and enhanced broad-spectrum disease resistance. Neither the genetic basis underlying flecking nor its possible relationship to disease resistance has been systematically evaluated. The commonly used maize inbred Mo17 has a mild flecking phenotype. The IBM-advanced intercross mapping population, derived from a cross between Mo17 and another commonly used inbred B73, has been used for mapping a number of traits in maize including several related to disease resistance. In this study, flecking was assessed in the IBM population over 6 environments. Several quantitative trait loci for flecking were identified, with the strongest one located on chromosome 6. Low but moderately significant correlations were observed between stronger flecking and higher disease resistance with respect to two diseases, southern leaf blight and northern leaf blight and between stronger flecking and a stronger defense response.