Both social support and stress predict depression in multiple sclerosis (MS) patients. Little work has been done on the relationship between positive life experiences and depression in this group. Ninety MS patients completed the Social Support Questionnaire (SSQ), the Hassles and Uplifts Scale (HUS), the Chicago Multiscale Depression Inventory (CMDI), and the Affective Reading Span Task (ARST). The Expanded Disability Status Scale (EDSS) was also used. Separate regression analyses were conducted with the EDSS entered at step 1, ARST memory bias score at step 2, SSQ at step 3, either Hassles or Uplifts at step 4, and the interaction term at step 5 to predict depression. Uplifts interacted significantly with social support to predict depression, but hassles did not. After considering disability level, memory bias, and social support and uplifts main effects, the interaction of uplifts and social support accounted for nearly 5% independent variance in depression (p < .05). These results suggest that the absence of uplifts, combined with low levels of social support, is related to depression in MS patients. More generally, these data indicate that it is important to study the absence of positive experiences along with stress and negative experiences in this population. (JINS, 2010, 16, 1039–1046.)