Single-breath technique (SBT) measurements of total respiratory resistance (Rrs) were compared with plethysmographic measurements of airway resistance (Raw) in healthy infants < or = 13 wk of age (Group 1; n = 49) and > 13 wk of age (Group 2; n = 37) and in infants > 13 wk of age with prior wheeze (Group 3; n = 49). A significantly higher percentage of Rrs (19%) than of Raw (2%) measurements were technically unsatisfactory, alinearity of the flow-volume curve accounting for 54% of Rrs failures. Although both Rrs and Raw were significantly higher in Group 3 infants, between-subject variability was wide in all groups. Rrs was significantly higher than initial expiratory (IE) Raw in all groups. Mean difference Rrs-IE Raw (95% CI) values were 1.98 (1.51, 2.48), 1.29 (0.96, 1.62), and 1.97 (1.56, 2.38) kPa.L-1.s for Groups 1, 2, and 3, respectively. Significant but smaller differences were seen for end-expiratory (EE) Raw in Groups 1 and 2 but not in Group 3. Mean difference Rrs-EE Raw (95% CI) values were 0.68 (0.11, 1.26), 0.55 (0.19, 0.92), and 0.31 (-0.06, 0.69) kPa.L-1.s for Groups 1, 2, and 3, respectively. Despite wide between-subject variability in Rrs and a relatively high failure rate, the SBT is simple to use, and it may be applicable to epidemiologic studies. However, clinical applications in individual infants may be limited by failure to detect the dynamic changes in resistance throughout the breath evident from plethysmographic studies.