Several neuroimaging studies have demonstrated compensatory cerebral responses consequent to sleep deprivation (SD), but all have focused on simple tasks with limited behavioral response options. We assessed the cerebral effects associated with SD during the performance of a complex, open-ended, dual-joystick, 3D navigation task (simulated orbital docking) in a cross-over protocol, with counterbalanced orders of normal sleep (NS) and a single night of total SD (approximately 27 h). Behavioral performance on multiple measures was comparable in the two sleep conditions. Functional magnetic resonance imaging revealed multiple compensatory SD > NS cerebral responses, including the posterior superior temporal sulcus [Brodmann area (BA) 39/22/37], prefrontal cortex (BA 9), lateral temporal cortex (BA 22/21), and right substantia nigra. Right posterior cingulate cortex (BA 31) exhibited NS > SD activity. Our findings extend the compensatory cerebral response hypothesis to complex, open-ended tasks.