Purpose: Although neonatal screening (or newborn screening) for cystic fibrosis (CF) is commonly practiced, systematic methods for accurate risk calculations are currently lacking. Methods and Results: We evaluated characteristics of the immunoreactive trypsinogen (IRT) test using the published data. The probability that a neonate has a positive IRT test, if the neonate is affected, a carrier, or a noncarrier, is Ϸ 1, 0.041, or 0.011, respectively. We provide methods to calculate genetic risks for a variety of commonly encountered scenarios in which neonates are positive by the IRT test. Conclusion: Our Bayesian methods permit CF disease probabilities to be calculated accurately, taking into account all relevant information. Genet Med 2005:7(5):317-327.