The effects of some local anesthetics on plasma protein secretion by rat liver slices have been studied and have been compared with those of colchicine. Rat liver slices were pulse-labelled with L-[14C]leucine for 9 min at 37 degrees C, collected on filter paper, washed with non-radioactive leucine and reincubated in the presence or absence of the drug to be tested. The radioactive plasma proteins produced were obtained by immunoprecipitation from either the chase medium or from the washed slices. Chlorpromazine, (3.10(-5) M), dibucaine (10(-5) M), lidocaine (10(-3) M) and procaine (5.10(-5) M) inhibited both the synthesis and secretion of plasma protein but did not affect the uptake of L-leucine into the slices nor the incorporation of phosphate into intracellular nucleotide phosphates or into phospholipids. The inhibition of secretion elicited by these drugs is probably not due to the inhibition of protein synthesis since cycloheximide, when added to the chase medium at a concentration which completely inhibits protein synthesis, did not inhibit plasma protein secretion, while cycloheximide plus procaine did inhibit secretion and also caused a retention of non-secreted plasma proteins within the slices. Unlike colchicine, however, procaine did not cause the retained plasma proteins to accumulate in Golgi-derived secretory vesicles, but showed a more general effect causing a distribution among several cell fractions.