Coping behaviors in individuals with multiple sclerosis (MS) or a spinal cord injury (SCI) were compared. Data were collected on 433 subjects with MS and 257 with SCI. Coping and illness uncertainty were measured by the Ways of Coping Checklist (revised) and the Mishel Uncertainty in Illness Scale. Results of the multivariate analysis of covariance indicated that there was no significant difference between the groups for the use of emotion-focused coping (EFC) or problem-focused coping (PFC). However, there was a significant difference in coping depending on illness uncertainty and the appraisal of life with a disability. Subjects used more EFC at high uncertainty and more PFC at no uncertainty compared to the other levels. When situations were appraised as dangerous, EFC was used more often, and when situations were appraised as an opportunity, PFC was used. The construct of vulnerability emerged as an important antecedent variable. When vulnerability was not included in the analysis, a spurious difference in EFC was found between the groups. Multiple regression results indicated that, for both groups, the choice of coping strategies had no significant effect in explaining emotional well-being while controlling for selected sociodemographic and disability-related variables.