The production of phosphoric acid by dehydrated process leads to the precipitation of unwanted insoluble salts promoting thus the crystallization fouling build-up on heat transfer surfaces of the exchangers. During the acid concentration operation, the presence of fouling in heat exchangers results in reducing the performance of this equipment, in terms of heat transfer, while increasing energy losses and damaging the apparatus. To mitigate these adverse effects of fouling, it is necessary to forecast the thermal resistance of fouling to schedule and perform exchanger cleaning. In this context, artificial neural network and response surface methodology were used to estimate thermal resistance of fouling in a cross-flow heat exchanger by using the operating data of the concentration loop. The absolute average relative deviations, mean squared errors, root mean squared errors and correlation coefficients were used as indicators error between the experimental and estimated values for both methods. The best fitted model derived from response surface methodology method was second order polynomial while the best architecture topology, for the artificial neural network method, consists of three layers: input layer with six input variables, hidden layer with six hidden neurons and an output layer with single output variable. The interactive influences of operating parameters which have significant effects on the fouling resistance were illustrated in detail. The value of correlation coefficient for the output parameter from the response surface methodology is 0.9976, indicating that the response surface methodology as an assessment methodology in estimating fouling resistance is more feasible compared with the artificial neural network approach.