Wallerian degeneration (WD) is the inflammatory response of the nervous system to axonal injury, primarily attributable to the production of cytokines, the mediator molecules of inflammation. We presently document the involvement of the inflammatory cytokines TNFα, interleukin (IL)-1α, and IL-1β in peripheral nerve (PNS) injury in C57/BL/6NHSD (C57/BL) mice that display the normal rapid progression of WD (rapid-WD) and C57/BL/6-WLD/OLA/NHSD mice that display abnormal slow progression of WD (slow-WD). TNFα and IL-1α mRNAs were expressed, whereas TNFα but not IL-1α protein was synthesized in intact PNS of C57/BL mice. TNFα and IL-1α protein synthesis and secretion were rapidly upregulated during rapid-WD in Schwann cells. IL-1β mRNA expression and protein synthesis and secretion were induced sequentially in Schwann cells with a delay after injury. Thereafter, recruited macrophages contributed to the production of TNFα, IL-1α, and IL-1β, which in turn augmented myelin phagocytosis by macrophages. Observations suggest that TNFα and IL-1α are the first cytokines with protein production that is upregulated during rapid-WD. TNFα and IL-1α may initiate, therefore, molecular and cellular events in rapid-WD (e.g., the production of additional cytokines and NGF). TNFα, IL-1α, and IL-1β may further regulate, indirectly, macrophage recruitment, myelin removal, regeneration, and neuropathic pain. In contrast to rapid-WD, the production of TNFα, IL-1α, and IL-1β protein was deficient in slow-WD, although their mRNAs were expressed. mRNA expression and protein production of TNFα, IL-1α, and IL-1β were differentially regulated during rapid-WD and slow-WD, suggesting that mRNA expression, by itself, is no indication of the functional involvement of cytokines in WD.