We investigated sex-related differences in task performance and brain activity in the orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) during performance of a decision-making task (the Iowa Gambling Task). When men and women were examined separately, men activated extensive regions of the right lateral OFC and right DLPFC, as well as the left lateral OFC. In contrast, women activated the left medial OFC. Examining sex differences directly, men showed better task performance and greater lateralized brain activity to the right hemisphere than women. This was exemplified by greater activation in a large area of the right lateral OFC of men during their performance of the Iowa Gambling Task. In contrast, women had greater activation in the left DLPFC, left medial frontal gyrus and temporal lobe during this task. Thus, brain mechanisms engaged by men and women when solving the same decision-making task are different. These observations indicate that sex-related differences contribute to the heterogeneity observed in both normal and abnormal brain functioning. These results also provide further evidence of sexual dimorphism in neurocognitive performance and brain function.