While a variety of methods exist to reconstruct ancestral sequences, all of them assume that a single phylogeny underlies all the positions in the alignment and therefore that recombination has not taken place. Using computer simulations we show that recombination can severely bias ancestral sequence reconstruction (ASR), and quantify this effect. If recombination is ignored, the ancestral sequences recovered can be quite distinct from the grand most recent common ancestor (GMRCA) of the sample and better resemble the concatenate of partial most recent common ancestors (MRCAs) at each recombination fragment. When independent phylogenetic trees are assumed for the different recombinant segments, the estimation of the fragment MRCAs improves significantly. Importantly, we show that recombination can change the biological predictions derived from ASRs carried out with real data. Given that recombination is widespread on nuclear genes and in particular in RNA viruses and some bacteria, the reconstruction of ancestral sequences in these cases should consider the potential impact of recombination and ideally be carried out using approaches that accommodate recombination.