yThese authors contributed equally to this work.

Evidence is mounting that epistasis is widespread among mutations. The cost of carrying two deleterious mutations, or the advantage of acquiring two beneficial alleles, is typically lower that the sum of their individual effects. Much less is known on epistasis between beneficial and deleterious mutations, even though this is key to the amount of genetic hitchhiking that may occur during evolution. This is particularly important in the context of antibiotic resistance: Most resistances are deleterious, but some can be beneficial and remarkably rifampicin resistance can emerge de novo in populations evolving without antibiotics. Here we show pervasive positive pairwise epistasis on Escherichia coli fitness between beneficial mutations, which confer resistance to rifampicin, and deleterious mutations, which confer resistance to streptomycin. We find that 65 % of double resistant strains outcompete sensitive bacteria in an environment devoid of antibiotics. Weak beneficial mutations may therefore overcome strong deleterious mutations and can even render double mutants strong competitors. Key words: epistasis, resistance, mutation. The effect of a mutation may depend on the genetic back-ground where it occurs, a phenomenon termed epistasis. The existence of pervasive epistasis for mutations that affect fitness-related traits has an important impact on the evolu-tionary dynamics of a population and the number of path