Multiple sclerosis (MS) is a chronic, unpredictable neurological disorder whose wide ranging symptoms and capricious disease course are known to produce considerable psychological stress. This study applied the Conservation of Research theory in building a prediction model to explain variability in perceived stress and coping within a sample of Americans with MS. The study sample consisted of 1,114 people with MS, 219 men (20%) and 895 women (80%), who participated in a national survey of the employment and psychosocial concerns of Americans with MS. Primarily Caucasian (75%), participants ranged in age from 20 to 87 years (M = 50.57, SD = 10.31). A backward stepwise multiple regression analysis revealed that women; non-Caucasians; younger people; those who had more difficulties meeting their financial obligations and who were less satisfied with their housing situations; people who reported lower levels of community and social life engagement; and those whose MS resulted in higher numbers of reported symptoms, lower levels of residual cognitive functioning, and lower levels of mobility impairment reported higher levels of perceived stress than did other participants. The aggregated predictors explained 41% of the variability in participants' stress ratings. The findings demonstrate the complexity in predicting how the onset and progression of MS affects an individual's psychological functioning.