Nitrogen removal via benthic denitrification in large river systems can be a significant sink of terrestrial nitrogen and a source of nitrous oxide (N2O) to the atmosphere. Recent studies have demonstrated the percent of in-stream nitrogen removed from a river reach is related to the water residence time. Here, we used the HYDRA aquatic transport model to examine whether in-stream nitrogen removal and the associated N2O emissions in the Mississippi River system during the 1960-94 period were sensitive to annual variability in climate. The results suggested an almost two-fold range in percent nitrogen removal 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 10 6 kg N) occurring in the wettest years. The results demonstrate the importance of considering climate variability and climate change in the management of nutrient export by large rivers.