In a single-blind, placebo-controlled study of 12 subjects diagnosed as having mild to moderate hypertension and hypercholesterolemia, pyrazinoylguanidine (PZG) in a dose of 600 mg twice daily for 4 weeks reduced systolic blood pressure and heart rate. Pyrazin-oylguanidine also reduced diastolic pressures, but to a lesser extent. Pyrazinovlguanidine reduced total serum cholesterol and low-density lipoprotein (LDL). Regression analysis indicated a dose-dependent reduction of both total cholesterol and LDL by PZG, i.e., the higher the presenting serum concentration, the greater the reduction by PZG. The extent of the reductions produced by PZG in elevated cholesterols and LDLs was highly correlated (r = .949). Normal high-density lipoprotein levels were unchanged by PZG. Pyrazin-oylguanidine increased 24-hour urine volume and urinary excretion of sodium. Serum Na⁺, K⁺, or Cl⁻ concentrations were unaltered. Means for plasma aldosterone and renin activities tended to decrease, but these trends did not attain statistical significance. Pyrazinoylguanidine was well tolerated. An activity profile that includes antihypertensive effects as well as reduction in hypercholesterolemia without major impact on serum renin or electrolyte balance makes PZG an attractive candidate for the management of hypertension.