Cocaine dependence is associated with orbitofrontal cortex (OFC)-dependent cognitive inflexibility in both humans and laboratory animals. A critical question is whether cocaine self-administration affects pre-existing individual differences in cognitive flexibility. Serotonin transporter knockout (5-HTT−/−) mice show improved cognitive flexibility in a visual reversal learning task, whereas 5-HTT−/− rats self-administer increased amounts of cocaine. Here we assessed: (1) whether 5-HTT−/− rats also show improved cognitive flexibility (next to mice); and (2) whether this is affected by cocaine self-administration, which is increased in these animals. Results confirmed that naïve 5-HTT−/− rats (n = 8) exhibit improved cognitive flexibility, as measured in a sucrose reinforced reversal learning task. A separate group of rats was subsequently trained to intravenously self-administer cocaine (0.5 mg/kg/infusion), and we observed that the 5-HTT−/− rats (n = 10) self-administered twice as much cocaine [632.7 mg/kg (±26.3)] compared with 5-HTT+/+ rats (n = 6) [352.3 mg/kg (±62.0)] over 50 1-hour sessions. Five weeks into withdrawal the cocaine-exposed animals were tested in the sucrose-reinforced reversal learning paradigm. Interestingly, like the naïve 5-HTT−/− rats, the cocaine exposed 5-HTT−/− rats displayed improved cognitive flexibility. In conclusion, we show that improved reversal learning in 5-HTT−/− rats reflects a pre-existing trait that is preserved during cocaine-withdrawal. As 5-HTT−/− rodents model the low activity s-allele of the human serotonin transporter-linked polymorphic region, these findings may have heuristic value in the treatment of s-allele cocaine addicts.