Background High numbers of employees are coping with affective disorders. At the same time, ambitiousness, achievement striving and a strong sense of personal control and responsibility are personality characteristics that are nowadays regarded as key to good work functioning, whereas social work circumstances tend to be neglected. However, it is largely unkown how personality characteristics and work circumstances affect work functioning when facing an affective disorder. Given the high burden of affective disorders on occupational health, we investigate these issues in the context of affective disorders and absenteeism from work. The principal aim of this paper is to examine whether particular personality characteristics that reflect self-governance (conscientiousness and mastery) and work circumstances (demands, control, support) influence the impact of affective disorders on long-term absenteeism (>10 working days). Methods Baseline and 1-year follow-up data from 1249 participants in the Netherlands Study of Depression and Anxiety (NESDA) in 2004–2006 was employed. Multivariate logistic regression analyses were performed, including interaction effects between depressive, anxiety, and comorbid disorders and personality and work circumstances. Results In general, mastery and conscientiousness increased nor diminished odds of subsequent long-term absenteeism, whereas higher job support significantly decreased these odds. Interaction effects showed that the impact of affective disorders on absenteeism was stronger for highly conscientious employees and for employees who experienced high job demands. Conclusions Affective disorders may particularly severely affect work functioning of employees who are highly conscientious or face high psychological job demands. Adjusting working conditions to their individual needs may prevent excessive work absence.