Disinfection of drinking water reduces pathogenic infection, but may pose risks to human health through the formation of disinfection byproducts. The effects of different factors on the formation of trihalomethanes were investigated using a statistically designed experimental program, and a predictive model for trihalomethanes formation was developed. Synthetic water samples with different factor levels were produced, and trihalomethanes concentrations were measured. A replicated fractional factorial design with center points was performed, and significant factors were identified through statistical analysis. A second-order trihalomethanes formation model was developed from 92 experiments, and the statistical adequacy was assessed through appropriate diagnostics. This model was validated using additional data from the Drinking Water Surveillance Program database and was applied to the Smiths Falls water supply system in Ontario, Canada. The model predictions were correlated strongly to the measured trihalomethanes, with correlations of 0.95 and 0.91, respectively. The resulting model can assist in analyzing risk-cost tradeoffs in the design and operation of water supply systems.