The effect of macrophage inactivation on lysolecithin-induced demyelination was studied. Adult rats were pretreated with a single intraperitoneal dose of 200 mg silica quartz dust, which selectively blocks the activity of circulating monocytes. Surgery was performed the following day and 2 microliters of 1% lysolecithin were injected intraspinally. The animals were perfused with aldehydes at 8 to 60 days postoperatively. Tissues were examined by optical and electron microscopy. The injection of lysolecithin produced a localized demyelinating lesion. Myelin debris in controls was phagocytosed by invading macrophages. Axons within the lesion appeared denuded. At later stages remyelination occurred. When animals were pretreated with silica, the macrophage response was remarkably reduced. The clearance of collapsed myelin was delayed. Accumulation of fluid within the sheaths resulted in tissue oedema and persistent spongiform changes. At 28 and 60 days postoperatively, increased fibrillary astrogliosis was observed but did not appear to interfere with remyelination. The findings of this study suggest that (a) active participation of macrophages is essential for the attainment of demyelination in the lysolecithin model and (b) treatment with silica prevents complete demyelination but has no apparent effect on remyelination.