In a case-control study in adult men from The Netherlands, the associations of work stressors with both exhaustion prior to first acute myocardial infarction (AMI) and with first AMI itself were explored. The 133 AMI-cases reported more exhaustion, work stressors, and smoking than the controls (i.e. 133 neighborhood controls and 192 hospital controls). After controlling for smoking, exhaustion constituted a firm risk indicator for first AMI; it was also positively associated with work stressors, in particular conflicts at work. Work stressors that may disrupt one's occupational career, and increased responsibility (in younger AMI-cases), were directly associated with elevated risk for first AMI. Conflicts at work were conducive to first AMI through their associations with exhaustion.