Unemployment has consistently been associated with increased risk of cardiovascular disease and premature mortality, and impaired autonomic modulation of the heart might be one mechanism partly explaining this. This study examined whether the possible effect of unemployment on cardiac autonomic modulation is in part mediated by lower psychological well-being. The sample comprised of 15 job-seeking men aged 30-49 years matched with 15 employed men on age, type of job, smoking habits, alcohol intake, frequency of physical activity, and body mass index. Heart rate variability (HRV) during a modified orthostatic test was the measure of cardiac autonomic modulation, and life satisfaction was the measure of psychological well-being. Unemployed men had significantly lower overall HRV (p = .040) than controls. This association was partially mediated through lower general life satisfaction, and in particular, by low financial satisfaction, independently of demographic and/or behavioral factors that influence HRV. These findings suggest that seeking a job is a potential stressor that may reduce overall HRV and contribute towards disturbance of cardiac autonomic modulation in men. Financial difficulties could be one mechanism through which the effects of unemployment are translated into impaired autonomic modulation.