BackgroundThe p factor represents the overall liability for the development of mental illness. While evidence supporting the p factor in adults has been reported, studies in children are fewer, and none have examined the p factor in children with chronic physical illness (CPI). ObjectiveWe aimed to model the p factor in a longitudinal sample of children with CPI using a parent-reported checklist and examine its construct validity against a structured diagnostic interview. MethodsWe used data from 263 children aged 2–16 years diagnosed with a CPI who were enrolled in the Multimorbidity in Children and Youth across the Life-course (MY LIFE) study. The p factor was modelled using the Emotional Behavioural Scales over 24 months using confirmatory factor analysis. Validation of the p factor was set against the Mini International Neuropsychiatric Interview for Children and Adolescents. ResultsFactorial evidence supported the p factor, modelled using a bi-factor structure, compared to a standard correlated-factors (i.e., two-factor) structure [Δχ2 = 9.66(4), p = 0.047]. p factor scores were correlated with the number of different mental illness diagnoses (r = 0.71) and total number of diagnoses (r = 0.72). Dose-response relationships were shown for the number of different diagnoses (p < 0.001) and total number of diagnoses (p < 0.001). ConclusionIn this first study of the p factor in children with CPI, we showed evidence of its bi-factor structure and associations with mental illness diagnoses. Mental comorbidity in children with CPI is pervasive and warrants transdiagnostic approaches to integrated pediatric care.