Effects of the tryptamine antagonist, cyproheptadine, as well as of amphetamine, chlordiazepoxide, and combinations of cyproheptadine with amphetamine on lever-pressing behavior of rats were determined. A multiple, fixed-interval, 2 min fixed-ratio, 15 response schedule of water presentation was used. The three drugs affected fixed-interval fixed-ratio responding in a rate-dependent way, lower rates being more increased whereas higher rates were relatively more decreased. Cyproheptadine increased low response rates to a lesser extent than amphetamine, but increased high response rates that were little affected or only decreased by amphetamine. The combination of cyproheptadine and amphetamine increased response rates to a higher extent than either of the drugs alone. In addition, the rate-suppressant effects of the highest doses of amphetamine were also enhanced by cyproheptadine. These results show that cyproheptadine can increase nonpunished responding and suggest that cyproheptadine and amphetamine act synergistically, but through different mechanisms, upon multiple fixed-interval fixed-ratio performance.