Effects of co-occurring disorders on work outcomes were explored among individuals with severe mental illness who were participating in a multisite randomized study of supported employment. At seven sites, 1,273 people were randomly assigned to an experimental supported employment program or a control condition and followed for 2 years. Multivariate regression analysis examined work outcomes including earnings, hours worked, and competitive employment, as well as whether psychiatric disability was disclosed to coworkers and supervisors. Individuals with any comorbidity had lower earnings and were less likely to work competitively. Those with physical comorbidities had lower earnings, worked fewer hours, and were less likely to work competitively. Disclosure was more likely among those with both cognitive and physical comorbidities, as well as those with learning disabilities. Competitive employment was less likely among those with intellectual disability, visual impairment, and human immunodeficiency virus/acquired immuno-deficiency syndrome. The experimental condition was positively related to all outcomes except disclosure. The results suggest that, with some exceptions, comorbidities affect employment outcomes, requiring tailored services and supports to promote vocational success.