The present study was designed to determine the efficiency of translocation of short polymers of arginine into vascular smooth muscle cells (VSMC) and to determine their effect on nitric oxide (NO) synthesis. Immunostaining revealed that heptamers of L-arginine (R7) rapidly translocated into the VSMC. This rapid transport was not observed with shorter polymers of L-arginine (R5) nor heptamers of lysine (K7). Translocation of R7 was not inhibited by the addition of free L-arginine into the media. When cells were transiently pretreated with R7 or a nonamer of arginine (R9), NO(2) production from cytokine stimulated VSMC was significantly increased, whereas incubation with R5 and K7 had no effect. Short polymers of arginine not only have a unique ability of rapid VSMC translocation but once internalized enhance NO production. Heptamers (or larger polypeptides) of arginine may be useful in therapy to enhance NO production in the vascular system.