We administered liposome-encapsulated antisense oligodeoxynucleotide targeted to angiotensinogen mRNA peripherally to spontaneously hypertensive rats to test whether peripheral angiotensinogen reduction would lower their hypertensive blood pressures and to determine the role of peripheral angiotensinogen in the modulation of hypertension. Using in vitro translation techniques, we tested the sequence specificity of the antisense sequence. The selected antisense sequence decreased angiotensinogen production in vitro, enabling us to distinguish between specific and nonspecific effects. To increase the efficiency of peripheral and hepatic antisense delivery, oligonucleotides were liposome encapsulated and intra-arterial administration. Confocal microscopy was used for determination of the hepatic distribution of fluorescently labeled antisense. Encapsulated antisense molecules were seen to be distributed within liver tissue 1 hour after injection; however, little or no uptake was observed with the unencapsulated oligonucleotides. We also determined the physiological effects of antisense oligodeoxynucleotide targeted to liver angiotensinogen mRNA. Administration of liposome-encapsulated antisense significantly decreased hypertensive blood pressures to normotensive levels compared with scrambled control oligonucleotides, unencapsulated antisense, and empty liposomes (P = .013). These data were supported by biochemical changes elicited by the antisense treatment. Rats receiving liposome-encapsulated antisense had significantly lowered peripheral angiotensinogen and angiotensin II levels compared with control groups (P < .05). No significant heart rate changes were observed in the antisense or control groups. These results suggest that peripheral angiotensinogen plays a role in the maintenance of hypertensive blood pressure in this model of hypertension and that peripheral administration of antisense molecules is possible with organ-targeted delivery mechanisms.