There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence. Display omitted •Virome-drug interactions were measured in a cohort of organ transplant recipients•The structure of the virome is strongly affected by immune modulation and antivirals•The total viral load increases markedly at the onset of the therapy•A potential application of the virome state in predicting immune strength is reported Using DNA sequencing of cell-free DNA extracted from plasma of organ transplant recipients, this paper investigates the response of the virome, the viral component of the microbiome, to the strong immune modulations.