The aim of this work was to investigate guar gum/ethylcellulose mix coated pellets for potential colon-specific drug delivery. The coated pellets, containing 5-fluorouracil as a model drug, were prepared in a fluidized bed coater by spraying the aqueous/ethanol dispersion mixture of guar gum and ethylcellulose. The lag time of drug release and release rate were adjustable by changing the ratio of guar gum to ethylcellulose and coat weight gain. In order to find the optimal coating formulation that was able to achieve drug targeting to the colon, the effect of two independent variables (the ratio of guar gum to ethylcellulose and the coat weight gain) on drug release characteristics was studied using 3×4 factorial design and response surface methodology. Results indicated that drug release rate decreased as the proportion of ethylcellulose in the hybrid coat and the coat weight gain increased. When the ratio of guar gum to ethylcellulose was kept in the range of 0.2 to 0.7, and the coat weight gain in the range of 250% to 500%, the coated pellets can keep intact for about 5 h in upper gastrointestine and achieve colon-specific drug delivery. The pellets prepared under optimal conditions resulted in delayed-release sigmoidal patterns with T5% (time for 5% drug release) of 5.1-7.8 h and T90% (time for 90% drug release) of 9.8-16.3 h. Further more, drug release was accelerated and T90% of the optimum formulation pellets decreased to 9.0-14.5 h in pH 6.5 phosphate buffer with hydrolase. It is concluded that mixed coating of guar gum and ethylcellulose is able to provide protection of the drug load in the upper gastrointestinal tract, while allowing enzymatic breakdown of the hybrid coat to release the drug load in the colon.