Little is known about quality of life (QOL) of patients with pancreatic cancer and their caregivers compared with adults with other cancers. This systematic review summarizes the available evidence base, identifies its limitations, and recommends directions for research and clinical application. A systematic review was conducted of research on QOL in adults with pancreatic cancer and their caregivers. Quality of life was examined in the following specific domains: psychological, physical, social, sexual, spiritual, and general. Of the 7130 articles reviewed, 36 studies met criteria for inclusion. Compared with healthy adults or population norms, adults with pancreatic cancer had worse QOL across all domains. Compared with patients with other cancer types, patients with pancreatic cancer evidenced worse psychological QOL. Physical and social QOL were either similar or more compromised than in patients with other cancers. Limited data preclude conclusions about sexual, spiritual, and caregiver QOL. Patients with pancreatic cancer evidence decrements in multiple QOL domains, with particular strain on psychological well-being. Methodological limitations of available studies restrict definitive conclusions. Future research with well-defined samples, appropriate statistical analyses, and longitudinal designs is needed. Findings from this review support the merits of distress screening, integration of mental health professionals into medical teams, and attention to caregiver burden.