Background: Pain and fatigue are recognized as critical symptoms that impact quality of life (QOL) in cancer, particularly in palliative care settings. Barriers to pain and fatigue relief have been classified into three categories: patient, professional, and system barriers. The overall objective of this study was to test the effects of a clinical intervention on reducing barriers to pain and fatigue management in oncology. Methods: This longitudinal, three-group, quasi-experimental study was conducted in three phases: phase 1 (usual care), phase 2 (intervention), and phase 3 (dissemination). A sample of 280 patients with breast, lung, colon, or prostate cancers, stage III and IV disease (80%), and a pain and/or fatigue of 4 or more (moderate to severe) were recruited. The intervention group received four educational sessions on pain/fatigue assessment and management, whereas the control group received usual care. Pain and fatigue barriers and patient knowledge were measured at baseline, 1 month, and 3 months post-accrual for all phases. A 3Ă2 repeated measures statistical design was utilized to derive a priori tests of immediate effects (baseline to 1 month) and sustained effects (baseline or 1 month to 3 months) for each major outcome variable, subscale, and/or scale score. Results: There were significant immediate and sustained effects of the intervention on pain and fatigue barriers as well as knowledge. Measurable improvements in QOL were found in physical and psychological well-being only. Conclusion: A clinical intervention was effective in reducing patient barriers to pain and fatigue management, increasing patient knowledge regarding pain and fatigue, and is feasible and acceptable to patients.