Life-threatening medical conditions such as severe combined immunodeficiency disease, leukemia, severe aplastic anemia, radiation injury, burns, organ transplantation, and aggressive administration of chemotherapy often necessitate the isolation of the patient in a protected germ-free environment for weeks or months. This treatment milieu has the effect of extensive psychological and physical isolation from family and staff. A review of the literature was undertaken to investigate the psychological implications of such treatment and to question the possibility that this isolation therapy might produce a unique type of psychological stress. Most authors agree that patients are able to withstand the emotional stress of germ-free isolation and that behavioral changes relate more to the severity of the illness rather than to the isolation. However, there may be inherent stresses related to isolator therapy that can be alleviated by environmental manipulation. Case vignettes are included and patient management in such an environment is outlined.