Fifty abstinent cocaine-dependent patients and 20 healthy controls were evaluated with 99mTc-HMPAO SPECT to examine gender differences in perfusion. Group contrasts with statistical parametric mapping revealed male and female patients exhibited not only different regions, but different types of perfusion abnormality, including decreased perfusion in the anterior cingulate/frontal regions among cocaine-dependent men, and increased perfusion in the posterior cingulate of cocaine-dependent women. The findings suggested that cocaine-dependent men have perfusion deficits previously associated with cocaine withdrawal and impaired response inhibition, whereas, cocaine-dependent women demonstrated perfusion abnormalities consistent with heightened stress responsivity and worse treatment outcome. The possibility of different neural mechanisms underlying relapse in men and women, and the implications for utilizing specialized treatments are discussed.