Cloned, L3T4+ T cells have been shown to respond to foreign protein antigens in the context of self-Ia glycoproteins and to non-self Ia glycoproteins. In the case of responses to foreign proteins, fixed antigen-presenting cells can present antigen fragments, but cannot present native proteins. Whether fixed allogenic cells can stimulate has been controversial. We have examined this question using a dual-reactive cloned helper-T-cell line. We find that conditions of fixation that block the presentation of native antigen to this cloned line, but which allow the presentation of antigen fragments, also allow presentation of allogeneic Ia molecules, leading to stimulation of the cloned line. This study also revealed an occult alloreactivity in the cloned T-cell line, which was expressed by fixed, but not by normal, antigen-presenting B lymphoma cells. All of these stimuli proceeded via the same clonotypic receptor, as determined by blocking with anti-T-cell receptor monoclonal antibody. These data suggest that responses to non-self Ia glycoproteins involve direct recognition of the allogeneic Ia molecules and do not require processing and presentation of these antigens by self Ia molecules.