Background: In this paper we present the approaches and methods employed in order to deal with a large scale multi-label semantic indexing task of biomedical papers. This work was mainly implemented within the context of the BioASQ challenge of 2014. Methods: The main contribution of this work is a multi-label ensemble method that incorporates a McNemar statistical significance test in order to validate the combination of the constituent machine learning algorithms. Some secondary contributions include a study on the temporal aspects of the BioASQ corpus (observations apply also to the BioASQ’s super-set, the PubMed articles collection) and the proper adaptation of the algorithms used to deal with this challenging classification task. Results: The ensemble method we developed is compared to other approaches in experimental scenarios with subsets of the BioASQ corpus giving positive results. During the BioASQ 2014 challenge we obtained the first place during the first batch and the third in the two following batches. Our success in the BioASQ challenge proved that a fully automated machine-learning approach, which does not implement any heuristics and rule-based approaches, can be highly competitive and outperform other approaches in similar challenging contexts.