Synthetic glycopeptides were used to study possible mechanisms for the reduction observed in the response of influenza virus-specific CD4+ T-cells to strains of virus in which amino acid substitution in the hemagglutinin has led to attachment of a carbohydrate side chain. The peptide NCTLIDALLGDPH stimulates vigorous proliferation of hemagglutinin-specific T-cell clones F1-36 and F1-40 but addition of a heptasaccharide, which approaches the size of natural carbohydrate antennae, eliminated the stimulatory capacity of the peptide. This occurs even though the site of carbohydrate attachment at the N-terminal asparagine lies outside the T-cell determinants encompassed by this sequence. A glycopeptide with only two sugar units was stimulatory for F1-36 but not F1-40, suggesting that peptides with a carbohydrate side chain are able to bind to MHC molecules but that approach of the T-cell receptor of certain clones to the glycopeptide-MHC complex is hindered. Loss of T-cell recognition following attachment of a long carbohydrate side-chain to T-cell determinants is not a general finding because attachment of six carbohydrate units to the peptide, NKYVKQNTLKLA, had little or no effect on the stimulation of a T-cell clone specific for this sequence.