During antigen presentation, a close association between CD4 and the T cell receptor (TCR) occurs as a result of interacting with the same major hlstocompatibllity complex class II molecule. The potential consequences of such an Intimate interaction on TCR specificity was addressed using CD4 loss variants of four different murine T cell hybrldomas specific for the Immunodominant hen egg lysozyme (HEL) peptlde 46–61. While all the CD4+ and CD4− variants tested possessed comparable surface expression of TCR, CD3, CD2 and LFA-1, and responded similarly to Immobilized antl-TCR and antl-CD3 monoclonal antibodies, they differed dramatically in their responses to either the naturally processed HEL antigen, synthetic peptide 46–61 or staphylococcal enterotoxln superantigens. While one hybridoma was comparatively unaffected by the loss of CD4, another lost Its responsiveness to antigen and peptide completely while retaining reactivity to SE. In contrast, two other hybrldomas still responded to antigen but lost reactivity to synthetic peptide and SE. These data could not be readily explained on the basis of affinity or signal transductlon requirements alone, and thus suggest that the intimate association of CD4 with the TCR may result in a subtle modulation of its fine specificity for some but not all T cells.