© 2015 John Wiley & Sons, Ltd. Objective: Enhancing implantation rates in preimplantation genetic diagnosis (PGD) cycles is still a challenging aspect to address. As aneuploidy can be one of the factors influencing the low implantation rates obtained, the aim of this work was to combine monogenic analysis with comprehensive aneuploidy screening (double factor) in order to transfer the selected (healthy and euploid) embryos in the same in-vitro fertilization (IVF) cycle. Method: In the present double-factor PGD (DF-PGD) approach, a single blastomere was biopsied from each embryo, and the whole genome amplification DNA product obtained was successfully used for both monogenic analysis and metaphase comparative genomic hybridization cytogenetic screening. The developed DF-PGD was applied to 62 embryos from seven families at risk for monogenic-inherited diseases in a total of seven IVF-DF-PGD cycles. Results: While 68.2% of the diagnosed embryos were healthy for the monogenic diseases, only 43.3% of them were chromosomally normal considering aneuploidies and/or segmental chromosome imbalances. Six out of seven families had transferrable embryos according to DF-PGD results. Two healthy babies were born from the 11 selected embryo transfers. Conclusion: In families at risk for monogenic diseases, the DF-PGD is a useful tool to select healthy and potentially viable embryos for transfer, according to their chromosome complement. What's already known about this topic? Aneuploidy can be one of the factors influencing the low implantation rates obtained in PGD cycles. Some years ago, double-factor PGD, (DF-PGD) in which monogenic analysis is performed simultaneously with a comprehensive cytogenetic analysis, was proposed to select best embryos for transfer in PGD cycles. However, two-blastomere biopsy was mandatory to perform this double analysis in the same IVF-PGD cycle, and therefore has only been sporadically applied. What does this study add? This study represents an improvement in double-factor PGD because the requirement of biopsying two cells has been overpassed. Both monogenic analysis and comprehensive aneuploidy screening have been performed from a single blastomere biopsy and in the same IVF-PGD cycle. An optimized DF-PGD procedure has been set-up, clinically applied and has achieved birth of healthy offspring.