Despite widespread use of transcutaneous PCO2 (TcPCO2) monitoring, the precise relationship between TcPCO2 and PaCO2 remains unclear. It has been widely assumed that theoretical correction of TcPCO2 (combining temperature correction with a constant metabolic factor of 4 mm Hg) accounts for the elevation of TcPCO2 over PaCO2. To test this assumption, TcPCO2 was measured with a 44°C electrode and compared to PaCO2 in 60 normotensive infants with cardiorespiratory disease during the first four ± six days of life (mean ± SD) (range one to 36 days). During hypocapnea, theoretically corrected TcPCO2 did not differ significantly from PaCO2. In contrast, during normocapnea, theoretically corrected TcPCO2 exceeded PaCO2 by 5 ± 4 mm Hg (P < .001), and similarly during hypercapnea, theoretically corrected TcPCO2 exceeded PaCO2 by 9 ± 6 mm Hg (P < .001). These data suggest that, as PaCO2 increases, there may be an imbalance between tissue CO2 production and removal, resulting in a progressively increasing gradient between TcPCO2 and PaCO2. Clarification of the relationship between TcPCO2 and PaCO2 should enhance the interpretation of TcPCO2 measurements in infants.