Considerable evidence has accumulated in the last decade to indicate that in addition to the mesolimbic dopamine system, serotonergic mechanisms may be involved in mediating the central effects of cocaine. Acutely, cocaine has been found to strongly inhibit serotonin uptake and increase extracellular serotonin, and repeated administration of cocaine has been shown to reduce serotonin levels in neurons. In order to test such evidence, a total of 125 African-American cocaine-dependent individuals who were receiving outpatient treatment were studied, along with 44 African-American controls recruited from local advertisements. Consenting and screening procedures were similar for all subjects, and control subjects were excluded if they had a history of substance abuse (except tobacco), a major psychiatric disorder, a positive urine drug screen, or were taking psychotropic medications. Tritiated paroxetine binding sites on platelets were assayed, and standardized assessments of behavior were performed. The outcome measures were number of negative urine drug screens, days in treatment, dropout rates, and number of treatment sessions attended. Cocaine patients were found to have significantly lower Bmax values of paroxetine binding compared to controls. Furthermore, Bmax values showed a significant positive correlation with days in treatment and negative urines. A combination of Bmax and Addiction Severity Index (ASI) employment scores improved the prediction of days in treatment, and a combination of Bmax and ASI drug scores enhanced the prediction of negative urines. These findings indicate that serotonergic mechanisms may be involved in cocaine dependence and may influence treatment outcome for cocaine patients. 1 table and 54 references