Alterations in the effect of a known encephalitogenic dose of myelin basic protein (MBP) when inoculated in combination with various myelin lipids have been examined in guinea pigs. A previous study demonstrated that, when MBP was given with galactocerebroside, it produced an acute autoimmune encephalomyelitis similar to that induced by whole white matter in which both inflammation and demyelination were features of the central nervous system lesions. MBP alone, on the other hand, resulted in inflammation only, without demyelination. The present study examined combinations of MBP with the myelin lipids galactocerebroside, sulfatide, ethanolamine phosphoglycerides, and serine phosphoglycerides. The lipids were given with or without MBP, in the same ratio as in intact central nervous system myelin, and were emulsified with complete Freund's adjuvant. An additional group received galactocerebroside and bovine serum albumin in complete Freund's adjuvant. These groups were compared with animals receiving either bovine white matter or MBP in complete Freund's adjuvant. Clinical autoimmune encephalomyelitis was observed in animals receiving bovine white matter, MBP, and all lipid-MBP emulsions; the bovine white matter, galactocerebroside/MBP, sulfatide/MBP, and ethanolamine phosphoglycerides/MBP groups demonstrated central nervous system lesions with a similar picture consisting of inflammation with demyelination, whereas inflammation without demyelination was seen in the MBP and serine phosphoglycerides/MBP groups. Thus, the addition of myelin lipids to MBP leads to the augmentation of demyelination in autoimmune encephalomyelitis lesions in the guinea pig. This might suggest that the immune response against MBP is enhanced by other myelin components. The relevance of these findings to human demyelinating disorders is discussed.