Estimating glomerular filtration rate (GFR) in severely ill inpatients is clinically important for therapeutic interventions and prognosis, but notoriously difficult to do accurately. The Modification of Diet in Renal Disease (MDRD) equation and Cockcroft-Gault (CG) formula are widely used to estimate renal function in sick hospitalized patients; however, neither method has been validated in this setting. Iodine 125-iothalamate clearances (iGFR) performed in 107 sick inpatients with renal dysfunction were compared with estimated GFRs (eGFRs) from the 6- and 4-variable MDRD (MDRD eGFR) and CG (CG eGFR) equations. Mean serum creatinine (SCr) level was 3.5 +/- 2.0 mg/dL (309 +/- 177 micromol/L), and mean iGFR was 17.1 +/- 17.9 mL/min/1.73 m2 (0.29 +/- 0.30 mL/s/1.73 m2). Six-variable MDRD eGFR was 22.5 +/- 17.4 mL/min/1.73 m2 (0.38 +/- 0.29 mL/s/1.73 m2), 4-variable MDRD eGFR was 23.9 +/- 16.3 mL/min/1.73 m2 (0.40 +/- 0.27 mL/s/1.73 m2), and CG eGFR was 26.0 +/- 17.1 mL/min/1.73 m2 (0.43 +/- 0.29 mL/s/1.73 m2). Blood urea nitrogen (BUN)/SCr ratios greater than 20 were seen in 58% of patients. Overall, the CG and MDRD equations overestimated iGFR, with poor agreement. Overestimation of at least 25% of measured iGFR was seen in 63%, 67%, and 70% of all inpatients when using the 6-variable MDRD, 4-variable MDRD, and CG equations, respectively. Accuracy of eGFR within 50% of measured iGFR was 55% for the 6-variable MDRD equation, 49% for the 4-variable MDRD equation, and 40% for the CG formula. The performance of both methods deteriorated further in patients with a BUN/SCr ratio greater than 20. Estimation equations are performed poorly compared with iGFR and are not reliable measures of actual level of function in sick hospitalized patients, especially those with a high BUN/SCr ratio. Although use of the 6-variable MDRD equation provides a better estimation of GFR, it still is unsuitable for clinical application in this population.