This paper studies the prediction of the output voltage reduction caused by degradation during nominal operating condition of a PEM fuel cell stack. It proposes a methodology based on Adaptive Neuro-Fuzzy Inference Systems (ANFIS) which use as input the measures of the fuel cell output voltage during operation. The paper presents the architecture of the ANFIS and studies the selection of its parameters. As the output voltage cannot be represented as a periodical signal, the paper proposes to predict its temporal variation which is then used to construct the prediction of the output voltage. The paper also proposes to split this signal in two components: normal operation and external perturbations. The second component cannot be predicted and then it is not used to train the ANFIS. The performance of the prediction is evaluated on the output voltage of two fuel cells during a long term operation (1000 h). Validation results suggest that the proposed technique is well adapted to predict degradation in fuel cell systems. Copyright (C) 2014, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.