Background Individuals with a strong family history of pancreatic cancer or a known hereditary cancer syndrome that is associated with pancreatic cancer are considered at high risk for developing pancreatic cancer. Living with a high risk for often fatal cancer is accompanied by high levels of uncertainty. Uncertainty is also independently associated with negative health outcomes. By understanding issues, sources, and responses to uncertainty, targeted supportive care strategies can be provided. Objectives This study aimed to examine how uncertainty manifests in the experience of being at high risk to develop pancreatic cancer and to describe issues, sources of, and responses to uncertainty. Methods In this secondary qualitative descriptive study, we analyzed 19 interviews with persons living with inherited pancreatic cancer risk. Analysis was guided by a conceptual framework of uncertainty and responses to uncertainty. Results Participants described multiple personal, practical, and scientific issues of uncertainty, centering on what to expect for their future health. Participants also expressed positive and negative cognitive, emotional, and behavioral responses to uncertainty, including engaging in surveillance. Uncertainty sources were both individual experiences as well as perceptions of healthcare provider uncertainty with managing pancreatic cancer risk. Conclusion Pancreatic cancer risk includes issues of uncertainty related to personal mortality, defining and managing risk, and experiencing surveillance. Positive and negative responses to this uncertainty could be targeted through interventions. Implication for Practice The oncology nurse should assess for sources of and responses to uncertainty in persons at risk for pancreatic cancer and offer psychosocial and educational support.