Metoclopramide (MCA) and procainamide (PCA), two widely used benzamide drugs developed before the present regulatory climate but recently found to induce DNA breaks in human lymphocytes, were evaluated for their genotoxic effects in cultured rodent and human cells. In subtoxic concentrations neither MCA (from 0.10 to 0.32 mM) nor PCA (from 0.18 to 0.56 mM) induced DNA fragmentation and repair in primary cultures of metabolically competent rat and human hepatocytes. In the absence of metabolic activation a meaningful increase in the frequency of 6-thioguanine-resistant V79 cells was produced by the maximum tolerated concentration of MCA (3.2 mM), whereas PCA resulted nonmutagenic. Any clastogenic effect was absent in human lymphocytes exposed to MCA for 28 hr, but a statistically significant increase in the frequency of micronucleated cells was observed when the exposure was prolonged to 72 hr. In contrast, PCA was never clastogenic under the same experimental conditions. These results suggest that of the two benzamides tested only MCA should be considered potentially capable of producing mutagenic and clastogenic effects; it presumably behaves as an agent which is rapidly transformed by the liver into inactive metabolites, and the clinical relevance of its genotoxic activity remains to be ascertained.