Induction of colitis in mice by a targeted mutation in the I110 gene is inbred strain dependent. C3H/ HeJBir (C3H) mice are colitis susceptible while C57BL/6J (B6) mice are resistant. Identification of quantitative trait loci (QTL) determining the differential strain responsiveness requires histopathologic scoring of multiple lesion subphenotypes in both cecum and colon. Here we show that ability to detect a major C3H-derived QTL on Chr 3 (cytokine deficiency-induced colitis susceptibility 1, Cdcs1) was critically dependent upon the degree of refinement of the histopathologic scoring system. QTL mapping was performed using a first-back-cross population of interleukin-10-deficient mice and applying two different grading systems to assess lesion subphenotypes. The same histological specimens were scored by two independent pathologists using either a very detailed scoring system for four subphenotypes developed at The Jackson Laboratory (TJL) or a simpler scoring system developed at the Hannover Medical School (MHH). The more detailed TJL subphenotyping protocol increased power to identify Cdcs1 (a maximum LOD score of 4.28 versus a LOD score of 1.77 when using the abbreviated MHH subphenotyping scoring system). This study shows that for QTL mapping in a mouse model of colitis, in which histology represents the gold standard for phenotyping, ability to detect linkage is critically dependent upon the degree of refinement adopted for separately scoring the multiple histopathologic lesions comprising this complex phenotype.