Chemical pleurodesis with tetracycline is frequently complicated by pleuritic chest pain. The most promising approach to control pain is to optimize the use of intrapleural lidocaine. While administering amounts of intrapleural lidocaine larger than commonly reported, we attempted to determine a safe and more effective dose, by using a subjective and objective assessment of pain, by measuring serum concentrations of lidocaine, and by observing patients for possible toxic effects of lidocaine. Chemical pleurodesis with tetracycline was performed on ten patients receiving an intrapleural dose of 200 mg of lidocaine (group 1) and on ten patients receiving a 250-mg dose (group 2). A significantly greater number of patients in group 2 were free of pain following pleurodesis (7/10 vs 1/10; p = 0.006). Of the 80 serum lidocaine levels obtained, only one value (6.1 micrograms/ml), in an asymptomatic patient in group 1, exceeded the therapeutic range (1.5 micrograms/ml to 5.5 micrograms/ml). One patient in group 2 experienced transient numbness of the right hand, a possible side effect of lidocaine. We conclude that to achieve optimum anesthesia during chemical pleurodesis with tetracycline, it is necessary to use doses of intrapleural lidocaine large than previously reported. Until the feasibility of a further escalation is demonstrated, 250 mg should be considered the standard dose.