1. The fractional clearance of lithium (FCLi) has been validated in the rat under controlled experimental conditions as a reliable indicator of sodium and water handling in the proximal tubule. The purpose of the present study was to evaluate some key methodological aspects related to the use of the FCLi in clinical and epidemiological investigation. 2. FCLi was determined in healthy normotensive, or in some cases, in borderline/mild essential hypertensive subjects, by a morning urine collection obtained between 09.00 and 13.00 hours after a 300 mg oral lithium carbonate load (= 8.1 mmol of elemental lithium). 3. The ratio of intra-individual to inter-individual variance of FCLi, measured in free-living subjects on unrestricted diet, was shown to be low enough (0.33) to allow adequate characterization of individuals in a population with a single measurement, or at most with two (compared with at least four measurements needed to characterize the fractional excretion of sodium). 4. The remarkable influence of dietary sodium intake on FCLi, demonstrated under metabolic ward conditions, might explain a major portion of the observed intra-individual variability. 5. At the dosage employed in the present study, oral lithium administration did not affect the renal handling of sodium, potassium or calcium. Likewise, it did not induce any change in a series of 17 metabolic parameters and indicators of renal and liver function. 6. It is concluded that the FCLi may be a safe and useful tool for the clinical and epidemiological investigation of renal sodium and water handling. The possibility of a confounding effect of dietary sodium intake, however, should be kept in mind.