Background: Accumulating evidence indicates that adenosine monophosphate (cAMP)‐dependent protein kinase A (PKA) is involved in the neurobiological responses to ethanol. Previous reports indicate that mice lacking the RIIβ subunit of PKA (RIIβ−/−) voluntarily consume more ethanol than wild‐type controls (RIIβ+/+) using 2‐bottle testing procedures. Although such procedures primarily measure consummatory behavior, operant self‐administration procedures allow analysis of consummatory as well as appetitive or “ethanol‐seeking” behavior (i.e., lever pressing is required to gain access to the ethanol solution). Therefore, we determined whether the high ethanol consumption characteristic of RIIβ−/− mice would be complemented by increased appetitive ethanol‐seeking behavior in an operant paradigm.Methods: RIIβ−/− (n=8) and RIIβ+/+ (n=8) mice were initially sucrose‐faded until they were lever responding for nonsweetened ethanol (10, 14, and 18%). Following the self‐administration testing, RIIβ+/+ and RIIβ−/− mice were given access to 2 bottles, one containing water and the other ethanol to replicate the voluntary ethanol drinking data previously from our laboratory. Finally, immediately after voluntary consumption all mice were again tested for self‐administration of 10% ethanol. Alterations in the reinforcement schedule were also explored as RIIβ+/+ and RIIβ−/− mice were tested for self‐administration of 10% ethanol at FR‐3 and FR‐5 schedules.Results: The RIIβ−/− mice displayed lower operant responding for ethanol and food reinforcement compared with RIIβ+/+ controls. However, this effect was driven by a significant increase in lever responses made by female RIIβ+/+ mice. When the excessive lever responses of the female RIIβ+/+ mice are accounted for, the RIIβ−/− mice show ethanol lever responses comparable to controls. Following operant self‐administration testing, RIIβ−/− mice of both sexes consumed more ethanol solution compared with RIIβ+/+ mice during 2‐bottle testing.Conclusions: Increased ingestion of ethanol by RIIβ−/− mice is likely the result of altered PKA activity within neuronal pathways that control ethanol‐consummatory behaviors. Conversely, the RIIβ subunit of PKA appears not to play a critical role in neuronal pathways that regulate appetitive behaviors directed at obtaining ethanol. Finally, increased operant self‐administration of food and ethanol by female wild‐type mice was absent in female RIIβ−/− mice, suggesting that normal PKA signaling may be part of a general, and sex‐dependent, mechanism involved with reinforcement‐seeking behavior.