BackgroundStress and stress hormones modulate memory formation in various ways that are relevant to our understanding of stress-related psychopathology, such as posttraumatic stress disorder (PTSD). Particular relevance is attributed to efficient memory formation sustained by the hippocampus and parahippocampus. This process is thought to reduce the occurrence of intrusions and flashbacks following trauma, but may be negatively affected by acute stress. Moreover, recent evidence suggests that the efficiency of visuo-spatial processing and learning based on the hippocampal area is related to PTSD symptoms.ObjectiveThe current study investigated the effect of acute stress on spatial configuration learning using a spatial contextual cueing task (SCCT) known to heavily rely on structures in the parahippocampus.MethodAcute stress was induced by subjecting participants (N = 34) to the Maastricht Acute Stress Test (MAST). Following a counterbalanced within-subject approach, the effects of stress and the ensuing hormonal (i.e., cortisol) activity on subsequent SCCT performance were compared to SCCT performance following a no-stress control condition.ResultsAcute stress did not impact SCCT learning overall, but opposing effects emerged for high versus low cortisol responders to the MAST. Learning scores following stress were reduced in low cortisol responders, while high cortisol-responding participants showed improved learning.ConclusionsThe effects of stress on spatial configuration learning were moderated by the magnitude of endogenous cortisol secretion. These findings suggest a possible mechanism by which cortisol responses serve an adaptive function during stress and trauma, and this may prove to be a promising route for future research in this area.