Patterns and processes involved in litter breakdown on desert river floodplains are not well understood. We used leafpacks containing Fremont cottonwood (Populus deltoides subsp. wislizenii) leaf litter to investigate the roles of weather and microclimate, flooding (immersion), and macroinvertebrates on litter organic matter (OM) and nitrogen (N) loss on a floodplain in a cool-temperate semi-arid environment (Yampa River, northwestern Colorado, USA). Total mass of N in fresh autumn litter fell by ∼20% over winter and spring, but in most cases there was no further N loss prior to termination of the study after 653 days exposure, including up to 20 days immersion during the spring flood pulse. Final OM mass was 10–40% of initial values. The pattern of OM and N losses suggested most N would be released outside the flood season, when retention within the floodplain would be likely. The exclusion of macroinvertebrates modestly reduced the rate of OM loss (by about 10%) but had no effect on N dynamics over nine months. Immersion in floodwater accelerated OM loss, but modest variation in litter quality did not affect the breakdown rate. These results are consistent with the concept that decomposition on desert floodplains progresses much as does litter processing in desert uplands, but with periodic bouts of processing typical of aquatic environments when litter is inundated by floodwaters. The strong dependence of litter breakdown rate on weather and floods means that climate change or river flow management can easily disrupt floodplain nutrient dynamics.