Perceived cognitive difficulties and cognitive impairment are important determinants of employment in people with multiple sclerosis (pwMS). However, it is not clear how they are related to adverse work outcomes and whether the relationship is influenced by depressive symptoms. Thus, this study examined perceived and actual general cognitive and prospective memory function, and cognitive appraisal accuracy, in relation to adverse work outcomes. The possible mediating and/or moderating role of depression was also examined. A cross-sectional community-based sample of 111 participants (33 males, 78 females) completed the Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ), Beck Depression Inventory – Fast Screen (BDI-FS), and questions related to their current or past employment. They then underwent cognitive testing using the Screening Examination for Cognitive Impairment, Auditory Consonant Trigrams test, Zoo Map Test, and Cambridge Prospective Memory Test. Perceived general cognitive and prospective memory difficulties in the workplace and performance on the respective cognitive tests were found to predict unemployment and reduced work hours since MS diagnosis due to MS. Depression was also related to reduced work hours, but it did not explain the relationship between perceived cognitive difficulties and the work outcomes. Nor was it related to cognitive test performance. The results highlight a need to address the perceptions of cognitive difficulties together with cognitive impairment and levels of depression in vocational rehabilitation programs in pwMS.