Purpose: People with a severe mental illness (SMI) are at particular risk of occupational exclusion. Among the approaches to occupational rehabilitation, supported employment (SE) has been proven to be the most effective. A requirement to enter SE-programs is that individuals must want to seek competitive employment. The aim of this work is to investigate the relationship between serious mental illness and the desire to work including potential predictors. Methods: This is a cross-sectional observational study of patients with SMI aged 18–65 years (n = 397). Patients were interviewed by trained staff using standardised instruments. The relationship between potential predictors and a strong preference for employment were analysed using a hierarchic binary logistic regression model. Results: Only about one-quarter (27.9%) of SMI patients is in competitive employment. Another quarter is unemployed (25.9%). Results show that the desire for competitive employment is strong among more than half of the SMI patients. Among the unemployed, two-thirds express a strong desire for work. These individuals are an ideal target group for SE interventions. Comorbid chronic physical illness, diagnosis, and the subjectively judged ability to work are associated with the desire for work. Conclusion: Our data confirm a substantial exclusion of individuals with SMI from the workforce. In general, care needs for workplace interventions are not being met and leave much room for improvement. In addition to employment status, the desire for work should be routinely assessed. Study registration: The study was registered in the German Clinical Trials Register (DRKS) (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015801) and under the WHO-Platform “International Clinical Trials Registry Platform” (ICTRP) (https://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00015801) under the registration number DRKS00015801 before the start of recruitment (Registration date: 21.02.2019).