RATIONALE: Alcohol use and major depressive disorder are frequently comorbid, with individuals diagnosed with a substance use disorder being nearly three times as likely to have major depression. Poor treatment responses are found for both disorders and are further complicated when they co-occur, underscoring the need for better therapies. One potential candidate is ketamine, which has been shown to have rapid and long-lasting effects in individuals with treatment-resistant depression and, in some studies, reduces drinking in alcohol use disorder. However, though women are more likely to have this comorbidity, few studies have examined sex-specific effects of ketamine on alcohol drinking, nor have studies assessed the potential for ketamine to reduce reinstatement of alcohol seeking. OBJECTIVES: The primary goal of the present studies was to determine the effects of ketamine on alcohol-motivated behaviors in male and female rats, including in a model of stress + cue-induced reinstatement of alcohol seeking using yohimbine (YOH). RESULTS: We found a selective reduction in alcohol self-administration and YOH + cue-induced reinstatement in females, but not males at a dose of 10 mg/kg ketamine. However, the same dose of ketamine was effective in reducing YOH + cue-induced reinstatement of saccharin seeking in both sexes. In addition, a different NMDAR antagonist, memantine, was effective in reducing alcohol seeking in both sexes, while the ketamine metabolite hydroxynorketamine (HNK) had no effects. CONCLUSIONS: In summary, these data suggest that antagonism of NMDARs may be effective in reducing stress-related alcohol seeking, but that ketamine has unique properties that lead to female-specific effects on alcohol seeking.