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L-Thyroxine (L-T4) is the treatment of choice of congenital hypothyroidism (CH). Longitudinal measurements of free T4 (FT4) serum concentrations were collected over the first two years of life with oral L-T4 treatment in infants with CH. Purpose of this study was to develop an integrated mathematical model to characterize the kinetics of exogenous L-Thyroxine (L-T4) after multiple dosing in infants with CH, and the dynamics of residual endogenous FT4 synthesis under treatment in the context of severe, moderate and mild disease. A total of 200 FT4 concentrations from 30 patients were available for analysis. At start of treatment, mean (standard deviation [SD]) postnatal age and weight of the population were 11 (8) days and 3.9 (1.3) kg. Mean (SD) pretreatment FT4 concentration was 11.3 (7.4) pmol/L. Measured FT4 concentrations were modelled as sum of residual endogenous FT4 and exogenously administered FT4 (L-T4). The integrated mathematical model consists of an absorption compartment for the exogenous FT4 administration, and a central compartment for measured FT4 with linear elimination. Hence, for residual endogenous and exogenous FT4 the same elimination rate constant was assumed. For the residual endogenous synthesis, different approaches were tested: a constant production and typical time-dependent production functions. FT4 data were analyzed using nonlinear mixed-effects modeling. The integrated mathematical model with a time-dependent non-linear Emax function describing a decreasing residual endogenous FT4 synthesis for increasing time provided the best data fit in terms of Akaike value and various goodness-of-fit plots. This is in line with the expected progressive suppression of the thyroid stimulating hormone by the exogenous FT4, and the subsequent decrease of residual FT4 endogenous synthesis. The developed mathematical model allows simulation of FT4 pharmacokinetic profiles for different disease severities and different dosing regimens.