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Objective To investigate the relationship of illness uncertainty (IU) to global psychological distress (GPD) and posttraumatic stress symptomatology (PTSS) using a path analysis approach. Methods Participants were 105 caregivers (MAge = 36.9 years, standard deviation [SD] = 8.7) of children (MAge = 8.6 years, SD = 5.0) with newly diagnosed cancer. A path analysis model examined the indirect and direct effects of each IU subscale on PTSS through GPD. Results The final model accounted for 47.30% of the variance in PTSS, and the ambiguity facet of IU had a significant indirect effect on PTSS through GPD. Lack of clarity and unpredictability were not significant predictors. Conclusions Ambiguity experienced by parents may be salient in the development of PTSS. Future research should examine these relationships longitudinally in larger samples to better understand adjustment in parents of children with cancer.