The cognitive task demands of office workers and the self-control demands of their work roles were measured in a sample of 196 employees in two different office layouts using a self-report questionnaire, which was circulated electronically. Multiple linear regression analysis revealed that both factors were associated with mental well-being, but not with physical well-being, while controlling for exposure to psychosocial stressors. The interaction between cognitive task demands and self-control demands had the strongest association with mental well-being, suggesting that the deleterious effect of one was greater when the other was present. An exploratory analysis revealed that the association was stronger for employees working in a large open-plan office than for those working in smaller offices with more privacy. Frustration of work goals was the cognitive task demand having the strongest negative impact on mental well-being. Methodological limitations and scale psychometrics (particularly the use of the NASA Task Load Index) are discussed. Statement of Relevance: Modern office work has high mental demands and low physical demands and there is a need to design offices to prevent adverse psychological reactions. It is shown that cognitive task demands interact with self-control demands to degrade mental well-being. The association was stronger in an open-plan office.