Fatigue is a common symptom associated with neuropathic pain (NP) and can have negative consequences on psychosocial functioning, physical endurance, and quality of life. Recent evidence indicates that immune activation modulated through the increased release of proinflammatory cytokines can predict fatigue in some patient populations. Although earlier studies have shown that immune activation is a pathophysiologic feature of NP, there have been no studies to examine the relationship between immune activation and fatigue in persons with NP. Therefore, the purpose of this exploratory study was to: 1) determine the relationships among fatigue, pain, psychosocial factors, and selected biologic markers of immune activation (interleukin [IL] 6 and soluble IL-6 receptor [sIL-6R]) in participants with persistent radiculopathy; and 2) determine the differences in these variables based on fatigue severity. Participants (n = 80) were classified according to their level of fatigue as low (27.5%), moderate (32.5%), or high (40%), and significant differences were found between fatigue categories (p = .001). Multivariate analyses of variance revealed that individuals with moderate to high levels of fatigue differed from those with the lowest levels of fatigue in psychologic distress, depressive symptoms, IL-6, and sIL-6R, whereas the differences between moderate and high levels of fatigue were significant for psychologic distress and sIL-6R only. The findings suggest that immune activation affects fatigue severity and possibly other behavioral responses, offering important information when providing care to patients with persistent radiculopathy. The integration of biobehavioral nursing interventions in pain management may have a greater impact on quality of life than treatment focused only on pain.