Using five different immortalized, cloned murine oligodendrocyte cells lines, we have assessed their sensitivity to the nitric oxide donor chemical S-nitroso, N-acetyl-DL-penicillamine (SNAP). The five lines were quite different in their sensitivity to SNAP as determined by assessment of viability, mitochondrial function, single-stranded DNA breaks, DNA/RNA/protein synthesis, morphology, and myelin gene expression. Single-stranded DNA breaks as well as mitochondrial and DNA damage occurred in viable cells. Thus, cell damage was independent of cell death. In the most mature oligodendrocyte cell line, cell morphology was altered and the expression of myelin basic protein mRNA was inhibited by nitric oxide in a time- and dose-dependent fashion. These findings suggest two things. First, oligodendrocytes at different states of differentiation are differentially sensitive to nitric oxide. Second, while not all oligodendrocytes may be destroyed in multiple sclerosis plaques, many could be significantly damaged and thereby nonfunctional in repair processes triggered during the pathology of this disease.