Evidence suggests that manipulating spatial information within working memory depends upon a circuitry organized around the prefrontal cortex (PFC) and the activity of the catecholamine systems. Other evidence attests to the effects of Delta-9 tetrahydrocannabinol (THC) on short-term spatial memory function, most probably involving CB(1) receptor activity within hippocampal circuitries. At the current time, there have been no systematic studies of the effects of THC on spatial working memory in human subjects using tasks known to depend upon frontotemporal neural circuitries. We examined the effects of a single sublingual 5 mg dose of THC on a test of spatial working memory (requiring active manipulation of remembered spatial information for the management of future behavior) and a test of spatial span (requiring only the reproduction of sequences of previously presented spatial cues). In all, 19 healthy adults were administered 5 mg THC and placebo in a double-blind, placebo-controlled, within-subject, crossover design. Male participants performed more accurately than female participants. THC significantly enhanced spatial working memory performance of female participants. By contrast, male and female participants produced more intrusion errors during performance of the Spatial Span task. These results suggest that THC has relatively complex effects on spatial memory in human subjects, perhaps reflecting altered CB(1) receptor activity within frontotemporal circuits or altered activity of mesocortical dopaminergic pathways in PFC areas associated with spatial memory.