1. The effects of histamine were investigated on mechanical and electrophysiological parameters in isolated electrically driven human ventricular papillary muscles. The effects of cimetidine and propranolol on histamine responses were also investigated. 2. The effects of histamine were compared with those of noradrenaline, isoprenaline, dimaprit, a selective H2-receptor agonist, and a cyclic AMP derivative, 8-(4-chlorphenylthio) cyclic AMP. 3. The effects of histamine and dimaprit and the effects of cimetidine on histamine responses were also investigated in guinea-pig right ventricular papillary muscles in order to allow a comparison with human papillary muscles. 4. In human papillary muscles, histamine caused concentration-dependent increases in the force of contraction and reductions in both time-to-peak tension and time-to-half-maximal relaxation. Histamine simultaneously caused distinct changes in the action potential configuration with increases in the height and duration of the plateau phase and an increase in the over-all action potential duration. 5. Noradrenaline and isoprenaline produced similar responses to histamine, as did 8-(4-chlorphenylthio) cyclic AMP, consistent with the view that the effects of histamine as well as the beta-adrenoceptor agonists on human ventricle, were associated with cyclic AMP mediated increases in calcium-dependent slow inward current.