Abstract: Antiviral drugs causing viral mutagenesis have shown value against a broad range of RNA viruses causing respiratory illnesses. While drug-induced accumulation of mutations generally decreases viral fitness, the potential for mutagenesis to generate escape variants is unknown and concerns have been raised about adaptive evolution promoting drug-resistance. We report prolonged treatment of a life-threatening RSV infection with a combination of two viral RNA-dependent RNA polymerase (RdRp) inhibitors, ribavirin and favipiravir, in a child with severe combined immunodeficiency undergoing haematopoietic stem cell transplantation. Viral deep sequencing of longitudinally collected RSV samples determined that ribavirin caused a 3-fold increase in the viral mutation rate. There was no synergistic effect upon addition of favipiravir. Viral load remained unchanged throughout antiviral treatment, but genomic modelling predicted loss of viral fitness secondary to drug-induced mutagenesis. The viral changes coincided with stabilisation of the patient’s clinical condition. In the absence of viral clearance, adaptive evolution occurred on a complex fitness landscape, leading to increased population diversity at the haplotype level. The evolutionary consequences of using mutagenic antiviral drugs are likely to be hard to predict, but in this example within-host virus evolution under extended treatment with mutagenic drugs resulted in an overall loss of viral fitness due to deleterious mutations accumulating faster than could be outweighed by positive selection. These genomic findings occurred in tandem with evidence of clinical improvement and are potentially associated.