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To better understand emotional information processing in pediatric inflammatory bowel disease (IBD) and its relationship with depression. Pediatric IBD is associated with higher rates of depression than seen in other physical diseases and in community samples. In systemic inflammation, proinflammatory cytokines have been implicated in altering activity in brain regions known to affect emotion processing and emotion regulation in depression.We examined differences in pupillary responses as a marker of brain function in response to negative emotional information in youths (ages, 8–17 years) with IBD both with (n = 8) and without (n = 15) comorbid depression and who were receiving high-dose steroid treatment. We compared their responses to each other and to depressed youths without IBD (n = 20) and healthy youths (n = 22).Youths with IBD demonstrated greater pupillary responses to the initial presentation of negative emotional stimuli, regardless of their depression status (p = .05). In contrast, depressed youths, regardless of their IBD status, demonstrated a greater constriction of the pupil 10 seconds to 12 seconds after exposure to negative stimuli. This constriction was associated with greater depressive severity and lower albumin levels.IBD may be associated with increased sensitivity to negative emotional stimuli above and beyond depression diagnosis. Depressed youths potentially demonstrate affective blunting, emotional avoidance, or a failure to regulate emotion after exposure to negative emotional information. Thus, there seem to be unique contributions of medical disease and depression to physiological indications of emotional reactivity, but these factors do not seem to interact.