The effects of caffeine on rate-force relation and their Ca++ dependence were studied in canine cardiac Purkinje fibers. At constant rate, caffeine increased and then decreased force. During drives at different rates (15, 60 and 120/min), 1 mM caffeine caused the largest positive inotropic effect at the slowest rate, but in 8.1 mM [Ca++]o caffeine no longer increased force even at 15/min. Interruptions of drive were followed by a positive and then a negative staircase: caffeine (1-4 mM) blunted these effects. A sudden decrease in rate caused a positive staircase: caffeine decreased and caffeine plus 8.1 mM [Ca++]o abolished it. A sudden increase in rate caused a negative staircase and on recovery a positive staircase: caffeine reduced and caffeine plus 8.1 mM [Ca++]o could reverse them. In low [Ca++]o (0.54 mM), caffeine caused only a positive inotropic effect and did not modify the rate-force relation patterns. High [Ca++]o ( > 8.1 mM) reversed the staircase patterns induced by a rate increase; adding caffeine shifted the reversal to lower [Ca++]o. Low [Na]o altered the rate-force relation similarly to high [Ca++]o, and caffeine exaggerated its effects. Decreasing [Ca++]i by means of tetrodotoxin or high [K+]o antagonized the caffeine effects on the rate-force relation. We conclude that caffeine markedly modulates the rate-force relation through a Ca(++)-dependent mechanism. This mechanism appears to involve a supraoptimal increase in [Ca++]i rather than a decrease in Ca++ released during the action potential.