PIP: This article discusses some of the issues raised by development of a new low-dose oral contraceptive (OC) now available in the US after 12 years of clinical use around the world. The principle of using as little of a therapeutic agent as possible to achieve the desired results is the rationale for low-dose OCs. It is very difficult to show a correlation of ambiguous side effects such as depression and mood changes and the dosage level. Some controversy accompanies efforts to reduce grave adverse reactions to OCs, primarily cardiovascular, by lowering the dose: doubts about the underlying epidemiological data result from the probable process of self-selection among women choosing OCs and changing prescription practices by physicians as well as the steady decline in frequency of serious cardiovascular problems, both of which create a shifting baseline. Thrombophlebitis has an even more ambiguous correlation: epidemiologists using clinical and hospital diagnostic records were apparently unaware of the considerable evidence which began to appear in the late 1950s on the unreliability of the clinical diagnosis of deep vein thrombosis. Mechanisms that may be involved in initiating cardiovascular accidents must be considered in the effort to demonstrate the beneficial effects of dosage reduction in a nonepidemiological manner. Little support remains for the notion that coagulation factor changes are important in the genesis of cardiovascular problems attributed to OCs, and the Framingham study, which is attempting to relate information on lipid factors predisposing to myocardial infarction to use of OCs, has not had a single myocardial infarction in a premenopausal woman. The role of lipoproteins among older OC users who smoke cannot however be dismissed and possible risk factors should be minimized even in the absence of detailed information. Other issues discussed are the apparent difference between metabolic transformation of the inactive isomer removed from norgestrel and the metabolism of the active compound, the near impossibility of detecting very small differences in contraceptive effectiveness, the importance of cycle control in determining acceptance of an OC, and the question of whether important beneficial side effects will persist as dosages are lowered.