In this study, the efficiency of adaptive neuro-fuzzy inference system (ANFIS) and genetic expression programming (GEP) in predicting the effects of infill walls on base reactions and roof drift of reinforced concrete frames were investigated. Current standards generally consider weight and fundamental period of structures in predicting base reactions and roof drift of structures by neglecting numbers of floors, bays, shear walls and infilled bays. Number of stories, number of bays in x and y directions, ratio of shear wall areas to the floor area, ratio of bays with infilled walls to total number bays and existence of open story were selected as parameters in GEP and ANFIS modeling. GEP and ANFIS have been widely used as alternative approaches to model complex systems. The effects of these parameters on base reactions and roof drift of RC frames were studied using 3D finite element method on 216 building models. Results obtained from 3D FEM models were used to in training and testing ANFIS and GEP models. In ANFIS and GEP models, number of floors, number of bays, ratio of shear walls and ratio of infilled bays were selected as input parameters, and base reactions and roof drifts were selected as output parameters. Results showed that the ANFIS and GEP models are capable of accurately predicting the base reactions and roof drifts of RC frames used in the training and testing phase of the study. The GEP model results better prediction compared to ANFIS model.