This two-volume set LNBI 10813 and LNBI 10814 constitutes the proceedings of the 6th International Work-Conference on Bioinformatics and Biomedical Engineering, IWBBIO 2018, held in Granada, Spain, in April 2018. The 88 regular papers presented were carefully reviewed and selected from 273 submissions. The scope of the conference spans the following areas: bioinformatics for healthcare and diseases; bioinformatics tools to integrate omics dataset and address biological question; challenges and advances in measurement and self-parametrization of complex biological systems; computational genomics; computational proteomics; computational systems for modelling biological processes; drug delivery system design aided by mathematical modelling and experiments; generation, management and biological insights from big data; high-throughput bioinformatic tools for medical genomics; next generation sequencing and sequence analysis; interpretable models in biomedicine and bioinformatics; little-big data. Reducing the complexity and facing uncertainty of highly underdetermined phenotype prediction problems; biomedical engineering; biomedical image analysis; biomedical signal analysis; challenges in smart and wearable sensor design for mobile health; and healthcare and diseases.