Two experiments investigated cardiovascular effects of mental fatigue as a function of (1) the difficulty of the cognitive challenge with which participants were confronted, and (2) the relevance of that challenge to the activity that instigated the fatigue. In the first, participants performed an easy (fatigue low) or difficult (fatigue high) counting task and then were presented an arithmetic challenge (task B relevance high) or a scanning challenge (task B relevance low) with instructions that they would avoid a noise if they attained a modest performance standard. Analysis of blood pressure responses assessed during the work periods revealed fatigue main effects, reflecting stronger responses for High Fatigue participants, regardless of the character of the second task. In the second, the procedure was the same except that it included a high performance standard and provided the chance to win a prize. Analysis of the pressure data revealed fatigue x work period interactions, reflecting relatively stronger responses among High Fatigue participants in work period 1, but relatively weaker responses among these participants in work period 2. Results confirm previous findings and support an analysis of fatigue influence on effort and associated cardiovascular responses. They also argue against the idea that mental fatigue influence may be confined to relevant cognitive performance realms.