We present a new method for estimating the overall organic aerosol (OA) formation rate at the regional scale using a chemical transport model (CTM), PMCAMx-2008, and an extensive set of measurements (Speciation Trends Network, Interagency Monitoring of Protected Visual Environments, Pittsburgh Air Quality Study, Southeastern Aerosol Research and Characterization) for the eastern United States. PMCAMx-2008 takes into account up-to-date OA formation theory including primary OA evaporation, updated secondary OA (SOA) yields from traditional volatile organic precursor gases and multigenerational oxidation chemistry (aging) of vapors from anthropogenic sources, which lowers the volatility of the OA distribution over time. An overall OA formation rate of 22 ± 5 ktons d−1 is consistent with available measurements for this summer time period. We perform an extensive sensitivity analysis of uncertain OA model processes to demonstrate the relationship between the estimated total OA production rate and model performance. Perturbing, within reasonable limits, emissions of volatile precursors, SOA yields from isoprene oxidation, and the solubility of organic vapors produces model predictions for total OA that deviate little from the base case performance. The fractional error and fractional bias vary by less than 6% and 13%, respectively. These cases also result in total OA formation rates within 5 ktons d−1 of the base case. Neglecting chemical aging of anthropogenic OA components results in OA levels significantly lower than the observations everywhere, while aging biogenic SOA with the same parameters used for the base case anthropogenic SOA aging results in overpredictions in both the South and Midwest United States. Aging biogenic and anthropogenic SOA together with a reduced aging reaction rate results in reasonable model performance and an OA formation rate of ∼23 ktons d−1. This suggests that even though uncertainties in the OA aging mechanism and other important parameters may lead to uncertainties in the contributions of specific OA formation pathways, the proposed approach may be used to infer upper and lower limits on the total OA mass formation rate.