We conducted a prospective study to describe the course of the pancreatic β-cell function from the time of clinical diagnosis of insulin-dependent (type I) diabetes to determine whether DR type, presence of islet cell antibodies (ICA), presence of insulin antibodies (IA), age at onset, and sex could help in the prediction of residual endogenous insulin secretion. A cohort of 68 children was followed for 18 mo after diagnosis of type I diabetes. The outcome variables selected for analysis were 1)serum C-peptide peak concentration after a Sustacal meal, 2) time of disappearance of the serum C-peptide response, and 3) time after diagnosis at which the maximal serum C-peptide response was observed. After institution of insulin therapy, serum C-peptide peak concentrations rose temporarily for 1–6 mo and declined thereafter. Multivariate analysis of the data showed that DR type (P = .2488) and presence of IA (P = .1604) had no effect on serum C-peptide over time, but sex (P = .0146), age at onset (P = .0002), and presence of ICA (P = .0147) significantly contributed to the variation of serum C-peptide over time. Furthermore, age at onset, presence of ICA, and sex were also the only significant predictors of the time of disappearance of the β-cell function. The relative risks of β-cell-function disappearance were 0.87 (P = .0015), 9.43 (P = .0181), and 2.25 (P = .0468), respectively. In conclusion, there are distinct variations in the natural course of the β-cell function in type I diabetes. β-Cell-function survival is significantly shortened the younger the subject is at disease onset, if ICA are present at diagnosis, and if the subject is male.