The humoral immune response of transplant recipients to influenza vaccination has been studied in detail. In contrast, the hemagglutinin inhibiting (HI) antibody response evoked by natural influenza infection and its impact on viral kinetics is unknown. In this prospective, multicenter, cohort study of natural influenza infection in transplant recipients, we measured HI antibody titers at presentation and 4 weeks later. Serial nasopharyngeal viral loads were determined using a quantitative influenza A polymerase chain reaction (PCR). We analyzed 196 transplant recipients with influenza infection. In the cohort of organ transplant patients with influenza A (n = 116), seropositivity rates for strain-specific antibodies were 44.0% (95% confidence interval [CI] 31.5-53.2%) at diagnosis and 64.7% (95% CI 55.4-72.9%) 4 weeks postinfection. Seroconversion was observed in 32.8% (95% CI 24.7-41.9%) of the cases. Lung transplant recipients were more likely to seroconvert (P = .002) and vaccine recipients were less likely to seroconvert (P = .024). A subset of patients (n = 30) who were unresponsive to prior vaccination were also unresponsive to natural infection. There was no correlation between viral kinetics and antibody response. This study provides novel data on the seroresponse to influenza infection in transplant patients and its relationship to a number of parameters including a prior vaccination status, virologic measures, and clinical variables.