To investigate differences in the pathologic processes between mutant C57BL/Ola (Ola) and normal C57BL/6J (6J) mice, the effect of acrylamide (ACR) on the degeneration and regeneration of myelinated fibers after crushing the sciatic nerve was morphometrically evaluated. Both Ola and 6J mice were treated with either ACR (subcutaneous injection of 50 mg/kg every other day for 13 days, n = 6) or physiological saline (n = 6). Morphometric evaluation of myelinated fibers of the sciatic nerve 5 mm distal to the proximal end of the crush site was performed systematically on day 14 of the crushing for each mouse. In Ola mice treated with either saline or ACR, large and small myelinated fibers remained without obvious progression of Wallerian degeneration, and degeneration of myelinated fibers was slower than in 6J mice. On the other hand, in 6J mice treated with either saline or ACR, many small myelinated fibers regenerated after degeneration and loss of both large and small myelinated fibers. In Ola mice, no statistically significant difference in the morphometric parameters was found between saline-treated and ACR-treated groups. Therefore, ACR did not have a significant effect on Wallerian degeneration of myelinated fibers in Ola mice. However, in 6J mice regenerated myelinated fibers were fewer in those receiving ACR than in those receiving saline. Therefore, ACR suppresses regeneration of myelinated fibers after crushing in 6J mice. A delay or partial failure of axonal sprouting and elongation may be responsible for the lower numbers of regenerated myelinated fibers. This study demonstrates the importance of the substrain differences in the degeneration and regeneration of myelinated fibers which may have implications for understanding the different susceptibilities to various neuropathies in man.