Females are more sensitive than males to the addictive effects of cocaine and are more likely to relapse. The nucleus accumbens has a well-established major role in the response to cocaine, and sex-specific differential expression of key transcripts at baseline and after cocaine withdrawal could underlie some of these differences. To address this hypothesis, four groups of mice (cycling females, ovariectomized females treated with estradiol or placebo and males) were evaluated for open field activity following 7 daily injections of saline or cocaine. Sensitization to the locomotor effects of cocaine was most pronounced in ovariectomized mice receiving estradiol, was greater in cycling females than in males, and failed to occur in ovariectomized/placebo mice. After a 28-day period of withdrawal, RNA prepared from the nucleus accumbens of individual cocaine or saline injected mice was subjected to RNASeq analysis. Expression of a substantial fraction of the transcripts expressed in the nucleus accumbens (~3%) differed in cycling female mice when compared to male mice, was altered by ovariectomy or was responsive to estradiol treatment. The transcripts differentially expressed in the nucleus accumbens of cycling female mice withdrawn from cocaine for 28-days exhibited substantial overlap with those differentially expressed in the nucleus accumbens of male mice withdrawn for 7-days. A small set of transcripts were similarly affected by cocaine in placebo or estradiol treated ovariectomized mice. Transcripts differentially expressed after 28-days of withdrawal encoded neprilysin, which degrades enkephalin and other neuropeptides, G protein coupled receptors and secreted proteins such as Wnt2, Fst and Igfbp4.