We report twenty-five patients with the acquired immunodeficiency syndrome (AIDS) and interface dermatitis. Patients with AIDS and interface dermatitis had numerous opportunistic and herpetic infections. Nearly all patients were receiving at least one medication prior to the development of their rash and many were clinically thought to have a drug eruption. When compared to skin biopsy specimens from non-AIDS patients with drug eruptions, specimens from patients with AIDS and interface dermatitis demonstrated a greater degree of vacuolar change, the frequent occurrence of necrotic keratinocytes, often in clumps, and the absence of eosinophils and polymorphonuclear leukocytes in the dermal infiltrates. Histologic and clinical features of our patients with AIDS and interface dermatitis are presented and contrasted with other interface dermatitides. Systemic and cutaneous immune abnormalities in patients with AIDS may be relevant to the pathogenesis of this interface process.