L-Arginine (L-Arg) affects various parameters that modulate the progression of renal disease. These same factors [e.g., glomerular filtration rate, changes in mesangial cell (MC) tension, and production of NO] are all controlled at least in part by changes in MC intracellular Ca²⁺ concentration ([Ca²⁺]_i). We therefore evaluated the effect of L-Arg on MC [Ca²⁺]_i. We found that L-Arg inhibits the vasopressin-stimulated rise in MC [Ca²⁺]_i both in rat and murine cell cultures. This effect does not appear to be due to metabolism of L-Arg to either NO or L-ornithine (L-Orn). Blocking the metabolism of L-Arg with N-monomethyl-L-arginine, an NO synthase inhibitor, or with 20 mM L-valine (L-Val), an inhibitor of Orn formation, does not reverse the inhibition. However, other cationic amino acids, as well guanidine, the functional group of L-Arg, all inhibit the vasopressin-stimulated rise in [Ca²⁺]_i, consistent with a structural basis for this effect. We conclude that 1) L-Arg inhibits vasopressin-stimulated murine and rat MC [Ca²⁺]_i rise, 2) this inhibition is not mediated by metabolism of L-Arg to either NO or L-Orn, and 3) the effect of L-Arg is due to its cationic functional group, guanidine.