Glomerular filtration rate is often used to assess the level of renal function and the progression of renal disease. However, the short-term effects of dietary protein restriction, blood pressure reduction, and specific classes of antihypertensive agents on GFR may be opposite in direction from their observed long-term beneficial effects on the progression of renal disease. The purpose of these analyses was to characterize these short-term effects and determine whether they can obscure the relationship between renal structure and function in patients with slowly progressive renal disease. The Modification of Diet in Renal Disease Study was a randomized trial of the effect of dietary protein restriction and strict blood pressure control on the decline in GFR in 840 patients with mean (range) baseline GFR of 36.1 (13 to 55) mL/min per 1.73 m2. In this study, comparisons of the randomized groups and correlational analyses were used to determine the short-term (4-month) effects on GFR of changes in protein intake, mean arterial pressure (MAP), and class of antihypertensive agents (computed as the reduction in GFR associated with starting versus stopping medications) during the first 4 months of follow-up and in subsequent 4-month intervals during the first 2 yr of follow-up. Combining results over the first 2 yr of follow-up, and controlling for changes in antihypertensive medications, the independent effect on GFR of changes in protein intake and MAP was 1.1 mL/min per 0.4 g/kg per day and 0.9 mL/min per 10 mm Hg, respectively (P < 0.001). These effects were observed in patients with increasing or decreasing protein intake or MAP, and in patients with stable or changing antihypertensive regimens. Starting treatment with diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors was associated with a 4.4-, 3.2-, or 2.2-mL/min greater GFR decline, respectively, than was stopping this treatment (P < 0.001). The effect of changes in protein intake, MAP, and diuretics was greater in patients with higher initial GFR. After controlling for initial GFR, there were no significant differences between the short-term effects observed during the first 4 months of follow-up and the short-term effects during subsequent follow-up. Changes in protein intake, blood pressure, and antihypertensive agents have small but statistically significant short-term effects on GFR. These effects can lead to clinically significant changes in renal function in patients undergoing multiple interventions and are large enough to confound the results of clinical trials in patients with slowly progressive renal disease. Future studies using GFR to assess the progression of renal disease should take into account these short-term effects when the length of follow-up is being planned.