Nonpoint-source pollutants are implicated in the global acidification of fresh waters. Our ability to differentiate the effects of point-source and nonpoint-source pollution on the acidification of large rivers is limited. Most studies of point-source discharges have been concerned with municipal programs for reducing biochemical oxygen demand, bacterial counts, and total phosphorus; few have addressed acidification of rivers. Because of the meager information on the role of nonpoint-source and industrial pollution in the acidification of large rivers, we examined long-term trends (and cyclic seasonal events) in pH, alkalinity, and selected ions in the lower Mississippi River basin from 1958 to 1986. Time-series analyses disclosed significant declines in pH and alkalinity and increases in strong acid anions in the lower 300 km (industrial corridor) of the lower Mississippi River. However, upstream from most industry on the Mississippi River and throughout the Atchafalaya River, where agricultural development has predominated, long-term trends in those characteristics were variable or nonsignificant.