Background The potential of abused drugs to induce addiction and compulsive drug-related behavior is associated with their ability to alter dopamine signaling. Dopamine plays a key role in reward signaling and it has been of great interest to investigate how various drugs of abuse alter reward-related behavior. Comparison with existing methods In rodents, the rewarding effects of drugs have often been assessed in self-administration or place preference paradigms; both involving repeated drug exposure and weeks of training and testing. New method Our investigation describes a valid approach to assess the initial rewarding effects of cocaine in mice with a single exposure place preference (sePP) paradigm, avoiding repeated drug injections. Results We present the sePP paradigm with a 3-day protocol to assess the initial rewarding effects of cocaine. Interestingly, only male mice exhibit sePP to cocaine. To assess subsequent drug-related behavior, the protocol was extended by 3 days of extinction followed by reinstatement on day 10. Conclusion The sePP paradigm provides a reliable and convenient approach to assess the initial rewarding effects of cocaine, circumventing the need for repeated drug injections. The sePP protocol allows further dissection of the mechanism and influence of initial cocaine exposure on subsequent drug-related behaviors by including extinction and reinstatement. The lack of sePP in female mice may reflect a biologically relevant sex difference in the initial subjective perception of cocaine-induced reward. This could relate to and explain why males and females have been reported to respond differently to cocaine and cocaine-associated cues.