Many methodological issues exist in human laboratory research with smoked cocaine-base that include safety, precision of dose delivery of smoked cocaine, and the lack of an adequate placebo. All of these issues are particularly apparent with studies involving multiple doses of cocaine. Addressing these concerns is important in conducting parametric studies that require examining dose-response effects. The purposes of this study were to determine: 1) the safest interval between doses to deliver smoked cocaine; 2) the accuracy or reproducibility of administering precise and multiple doses of cocaine; 3) the potential for using a control dose of cocaine; and 4) the influence of multiple doses on these parameters. Six black males were given 10 doses of either 5 or 35 mg of cocaine-base at 15-, 30-, and 45-min intervals. The dependent measures included physiological, subjective, and performance responses. These measures were taken prior to dosing and at specific time intervals after each dose of smoked cocaine. The results showed: 1) dosing at 30-min intervals allowed sufficient time for recovery of blood pressure and heart rate to permit up to 10 doses to be safely administered; 2) reproducible blood cocaine levels were obtained with repeated dosing using a heated wire-coil device; 3) significant differences were observed between the 5- and 35-mg dose with 5 mg being a low enough dose to produce minimal effects; 4) acute tolerance was evidenced with multiple doses of cocaine for most of the measures; and 5) considerable between- and within-subject variability was observed in the pattern of responses to cocaine.