Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are chronic immunologic diseases that can cause cognitive dysfunction. MS is a central nervous system (CNS) disease characterized by demyelination and progressive brain atrophy. SLE is an autoimmune disease capable of damaging multiple organ systems, including the CNS. Cognitive disturbances are seen in both SLE and MS. The present study is concerned with understanding the similarities and differences between the cognitive profiles of SLE and MS as well as the relationship between cognitive impairment and vocational disability in these patients. We examined 47 SLE patients, 47 MS patients, and 44 healthy controls. The groups were well matched on demographics and the patient groups were also matched on disease duration and severity. Group comparisons revealed that generative verbal fluency and visual-spatial memory are more profoundly affected in MS than SLE; whereas depression, fatigue, and working memory deficits are similarly involved in both diseases. Logistic regression analysis revealed that executive function, in particular, was predictive of vocational outcomes in SLE and MS patients.