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To establish the typical error (TE) associated with equipment, testing, and biological variation of a running economy (RE) test in 11 elite male distance runners (V̇O2max 70.3 ± 7.3 mL·min−1·kg−1), and measure the between-athlete variation of 70 highly trained runners (V̇O2max 69.7 ± 6.0 mL·min−1·kg−1) to determine the magnitude of the smallest worthwhile change (SWC) required for RE.Runners performed three 4-min bouts of submaximal treadmill running at speeds of 14, 16, and 18 km·h−1 (0% grade), on two separate occasions within a 7-d period to determine reliability and once over a 3-yr period to measure the SWC. During all RE tests O2 consumption (V̇O2), ventilation (V̇E), respiratory exchange ratio (RER), heart rate (HR), stride rate (SR), and concentration of blood lactate (Lac) were determined.The TE for the pooled data of three running speeds (14, 16, and 18 km·h−1) was 2.4% for V̇O2, 7.3% for V̇E, 27% for Lac, and ranged between 1 and 4% for RER, HR, and SR.The results demonstrate that although the magnitude of the TE for a submaximal treadmill running protocol of three 4-min work efforts is small (2.4–7.3%) for measures associated with cardiorespiratory parameters, it is three- to fourfold higher for Lac. Given the small TE associated with RE, and a SWC of similar magnitude for this cohort of distance runners, the RE test is useful in detecting changes attributable to training interventions. Changes in RE greater than ∼2.4% in this cohort of elite distance runners are likely to be “real” and “worthwhile,” and not simply related to testing error and typical variation.