Reye's Syndrome (RS) is characterized by encephalopathy, fatty degeneration of viscera and high levels of free fatty acids which are implicated in cellular toxicity. We have examined the effects of octanoic acid (C8:0), palmitic acid (C16:0) and oleic acid (C18:1) on rat liver mitochondrial swelling by spectroscopic and microscopic techniques. Of the fatty acids tested oleic acid had a greater effect than palmitic acid while octanoic acid had no effect. Acyl-CoA derivatives produced greater mitochondrial swelling than either acyl-carnitine or free fatty acids. However, identical amounts of palmitoyl-CoA and oleoyl-CoA were required to produce the same degree of swelling. Addition of carnitine (2mM) to oleoyl-CoA reduced the mitochondrial swelling significantly thus suggesting that the toxicity of the fatty acids may be reduced by conversion to their carnitine derivatives. Twice the concentration of oleoyl-carnitine was required to produce half the maximum swelling as compared to oleoyl-CoA. Ultrastructural profiles of mitochondria treated with oleic acid, oleoyl-CoA and oleoyl-carnitine demonstrated greater swelling with oleoyl-CoA than with oleic acid or oleoyl-carnitine. These results suggest that carnitine may protect the mitochondria from damage by the fatty acids and their acyl-CoA derivatives in Reye's Syndrome.