1. Our aim was to determine the influence of the type of task, the absolute and relative difficulty of the task, and the perceived stress associated with performance of the task on sympathetic circulatory regulation during cognitive challenge in humans. 2. Sympathetic nerve activity to skeletal muscle (MSNA) determined from peroneal microneurography, heart rate and arterial blood pressure were recorded continuously in twelve subjects during a modified Stroop colour word test (CWT) and mental arithmetic (MA), each performed over six levels of increasing absolute task difficulty. Performance (percentage correct) on each task was assessed and ratings of perceived stress obtained. Responses to CWT and MA were compared at similar levels of performance and perceived stress. 3. MSNA decreased at task onset, remained below baseline levels at low levels of difficulty which were not perceived as stressful, increased above baseline levels at higher levels of difficulty which were perceived as stressful, and increased further during recovery. Thus, the regulation of MSNA was stress dependent. At similar levels of stress perception there were no differences in MSNA between CWT and MA. Although performance declined as task difficulty increased, there was no particular 'threshold' level of performance associated with the stimulation of MSNA. 4. Arterial pressure and heart rate were elevated above baseline levels throughout the mental tasks. Arterial pressure increased over the first 3-4 levels of each task and then plateaued whereas heart rate did not vary across increasing levels of task difficulty. Heart rate and arterial pressure responses to CWT were higher than those to MA. 5. These data demonstrate that during cognitive challenge the stimulation of MSNA is governed primarily by perceived stress which is dependent, in part, on the absolute level of task difficulty. In contrast, neither performance nor the type of cognitive task appear to be important determinants of MSNA. Arterial pressure is influenced by the task and level of difficulty. Heart rate is independent of task difficulty but may be task dependent.