Nitrogen (N) removal via benthic denitrification in large river systems can be a significant sink of terrestrial N and a source of nitrous oxide (N2O) to the atmosphere. Recent studies have demonstrated the fraction of in-stream N removed from a river reach is related to the water residence time. We used the HYDRA aquatic transport model to examine the sensitivity of in-stream N removal and the associated N2O emissions in the Mississippi River system to the interannual variability in climate. The results suggested an almost two-fold range in the percent of N removed in the Mississippi River system and a three-fold range in the associated N2O emissions, with the lowest percent removed (10--33%) and the highest N2O emissions (15.5--26.0 106 kg N) occurring in the wettest years. The results demonstrate the importance of considering climate variability and change in the management of nutrient export by large rivers.