The drug self-administration paradigm is routinely used to assess the abuse liability of psychoactive compounds. Investigations of the behavioral effects of drug use, however, often involve the response-independent (experiment-delivered) administration of the compound. It is frequently assumed that response-independent presentation of a compound has the same effects as response dependent deliveries. The present study examined directly the effects of response-dependent (self-administered) versus response-independent (experimenter-delivered) administration of cocaine on food intake and lethality. Littermate triads were exposed to either cocaine (0.33 mg/infusion) or saline using a yoked-box procedure. One member of the triad self-administered the drug under a fixed-ratio 2 schedule. The other two rats received response-independent infusions of either cocaine or saline. Groups of triads were exposed to two different cocaine access conditions. Daily sessions were terminated after 6 h for one group and after the delivery of 80 infusions for the other. The mean number of infusions delivered each session was 47 (+/- 12) and 70 (+/- 11), respectively, for the 6-h and 80-infusion condition. Under the 80-infusion condition, response-independent infusions of cocaine resulted in a significantly higher rate of mortality compared to littermates self-administering identical amounts of the drug. A fewer number of deaths occurred under 6-h condition; however, only rats exposed to response-independent infusions died under both access conditions. These data indicate that the presence or absence of response dependency can profoundly alter the lethal effects of cocaine.