One of the key pathologies associated with central white matter axons is disruption of the myelin sheath that surrounds axons, which can manifest either as demyelination, where existing myelin breaks down, or dysmyelination, where myelin formation is abnormally affected. Myelin pathologies affecting the central nervous system include the inflammatory condition multiple sclerosis resulting in focal lesions, genetic abnormalities resulting in more generalized hypomyelination such as the leukodystrophies and developmental pathologies such as periventricular leukomalacia. Focal demyelination can also result from swelling of the axon underlying the myelin, where the physical expansion of the axon disrupts the integrity of the myelin sheath, or as a consequence of axonal demise. Pathology of myelin is an important clinical condition as the constancy of action potential conduction in the central nervous system (CNS) relies on uniform axon diameter, coupled with fidelity of the overlying myelin providing high resistance, low capacitance insulation. Whereas the effects of demyelination on conduction have been extensively studied/modeled, equivalent studies on the repercussions for conduction of axon swelling, a common early pathological feature of (potentially reversible) axonal injury, are lacking. The recent description of experimentally acquired morphological and electrical properties of small CNS axons and oligodendrocytes prompted us to incorporate these data into a computer model, with the aim of simulating the effects of focal axon swelling on action potential conduction. Demyelination of complete internodal regions caused decreased conduction velocity the degree of attenuation commensurate with degree and extent of demyelination. A single swelling on an otherwise intact axon, as occurs in optic nerve axons of Cnp1 null mice caused a small decrease in conduction velocity. The presence of single swellings on multiple contiguous internodal regions (INR), as likely occurs in advanced disease, caused qualitatively similar results, except the dimensions of the swellings required to produce equivalent attenuation of conduction were significantly decreased. Our simulations of the consequences of metabolic insult to axons, namely the appearance of multiple swollen regions, accompanied by perturbation of overlying myelin and increased axolemmal permeability, contained within a single INR, revealed that conduction block occurred when the dimensions of the simulated swellings were within the limits of those measured experimentally, suggesting multiple swellings on a single axon could contribute to axonal dysfunction, and that increased axolemmal permeability is the decisive factor that promotes conduction block. Keywords: axonal spheroid, myelin, aglycemia, permeability