The search for a highly selective progestin that exerts a potent and targeted progestational response with minimal or absent androgenic effect has paralleled investigation into the possible impact of these agents on cardiovascular disease in women. Such a progestin, norgestimate (NGM), in a dose of 250 micrograms, has been combined with ethinyl estradiol (EE) 35 micrograms in a new oral contraceptive (OC), Ortho-Cyclen or Cilest. Results of two long-term, multicentric clinical trials demonstrate that this formulation is comparable in efficacy to the norgestrel-containing OC Lo/Ovral. There were no statistically significant differences in pregnancy rate, and both OCs were well-tolerated in a large and diverse study population. In several areas, however, the inherently lower androgenicity of the norgestimate OC produced clinical changes compared with the norgestrel formulation. These changes were primarily evident in the more natural menstrual patterns with the norgestimate OC, its less severe impact on the endometrium, and, most important, its positive impact on lipoprotein metabolism. NGM/EE consistently produced statistically significant increases in high density lipoprotein (HDL) and concomitant improvement in the ratio of low density lipoprotein (LDL) to HDL. By cycle 24, this highly predictive parameter of atherosclerotic risk had decreased 7.7% in the NGM/EE group. Conversely, the norgestrel-containing formulation resulted in statistically significant decreases in HDL and increases in the LDL/HDL ratio; by cycle 24, these patients showed an 18.5% increase in the LDL/HDL ratio. All between regimen comparisons of mean changes in the LDL/HDL ratio were statistically significant, from baseline through cycles 3, 6, 12 and 24.