In the Hypertension Detection and Follow-up Program (HDFP), elevated blood pressure (BP) was treated by rigorous, stepped care (SC) therapy among half the participants, while the other half were referred to usual sources of care (referred care, RC). There was no program to reduce weight, however, some participants changed weight voluntarily over the first 2 yr, providing an opportunity to examine the role of weight change in the development of diuretic-induced hyperuricemia, hyperglycemia and hypercholesterolemia. There was a stepwise progression from decreased glucose, uric acid and cholesterol concentrations, and BP associated with maximum weight loss to increased values with maximum weight gain. In SC, systolic BP declined by 22.4% among weight-losers and by 17.1% among weight-gainers; in RC, it was 14.4 and 8.1%, respectively. The pattern in diastolic blood pressure and weight change was similar but not as marked. These findings suggest the potential importance of weight loss in enhancing effectiveness of antihypertensive drug treatment and attenuating increases in glucose, uric acid, and cholesterol associated with diuretic treatment of hypertension. The weight change analyses are based on postrandomization observations and do not reflect experimental changes.