A complex, stochastic simulation model of Colorectal Cancer (CRC) is examined through factor screening to determine which factors in the model are important. The factor screening employs a Resolution IV 2k Fractional Factorial experimental design. The factors are examined in terms of their impact on cost, quality-adjusted lifeyears (QALY), and cost per QALYs. Out of 72 factors, eight factors were determined to be most important and observed as “driving factors” in the CRC model. Surprisingly these factors were consistently important for all outcomes. However the limitations of the experimental design may have constrained the important factors to factors related only to the natural history of the disease and therefore subject to minimal control.