There is mounting evidence that low levels of some polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of depressive and aggressive disorders, including homicides. There is also evidence derived mostly from the animal literature that PUFAs could play a role in the abuse of substances through their action on central serotonergic and dopaminergic systems that are both known to play a role in reward mechanisms. In this study, we explored the possibility that the relapse rates of cocaine addicts discharged after a period of detoxification on an inpatient unit would be associated with their PUFA status. Thirty-eight patients were enrolled in the study. PUFA status was assessed only at baseline, shortly after admission. Resumption of substance use was assessed 3 months, 6 months and 1 year following discharge. Thirty-two patients remained available for follow-up for the duration of the study. Subjects who relapsed at 3 months had significantly lower baseline levels of total n-6 PUFAs, linoleic acid (LA, 18:2n-6), arachidonic acid (AA, 20:4n-6) and total n-3 PUFAs when compared to non-relapsers by ANCOVAs with age and weight as covariates. Lower baseline total n-6 PUFAs, LA and AA continued to predict relapse 6 months and 12 months following discharge. Age, marital status, educational level, cocaine use parameters or psychopathology did not differ between relapsers and non-relapsers. In conclusion, low PUFA status at baseline was a better predictor of relapse than cocaine use, sociodemographic or clinical parameters. These data suggest, but do not prove, the existence of a causal relationship between n-6 or n-3 status and relapse vulnerability in cocaine addicts, and provide a rationale for the exploration of possible relationships between relapse to addictive disorders and PUFA status in observational and interventional trials.