Significance The same mutation can have different effects among individuals, and one reason for this is the presence of additional mutations, a relationship known as epistasis. Epistatic effects are difficult to predict. We report a rare example of positive epistasis between a silent mutation (that changes nucleotide but not the encoded amino acid) and missense mutation(s) (that change amino acid and cause cystic fibrosis disease). Individually, each mutation has a detrimental effect, but they are beneficial when present together. The underlying molecular effect is in their ability to markedly modulate the ribosomal speed on mRNA in a synergistic fashion. In a broader setting of human diseases, our results suggest that epistasis with silent mutation broadens the spectrum of disease outcome.