Giant reed is one of the most widespread invasive species in riparian habitats in California and other coastal states of the United States. This species is thought to spread primarily asexually by flood dispersal of stem and rhizome pieces; viable seeds have not been found in the United States. Research was conducted to quantify genetic variation in giant reed along the Santa Ana River in California and to investigate the pattern of distribution of variation along this watershed. Populations at least 3.2 km apart were collected along the length of the Santa Ana River from the headwaters to the Pacific Ocean. One additional population from a different watershed was collected to serve as an out-group. Genetic analyses were conducted using both starch gel electrophoresis for isozyme analysis and random amplified polymorphic DNA (RAPD) analysis. Both isozyme and RAPD analyses revealed levels of genetic diversity comparable with those in the literature for clonal species, suggesting that asexual reproduction is the primary means of spread of giant reed. Most phenotypes were spread along the Santa Ana River, which is expected if water is the primary means of spread of vegetative propagules. Among the unique phenotypes found, two isozyme phenotypes and one RAPD phenotype were dominant and were found spread along the river, which may indicate greater fitness or competitive superiority to the other phenotypes that were less common. The dominant phenotypes were also found in the out-group population, possibly because of spread by humans. Because spread occurs mainly asexually, management efforts should focus on preventing establishment and spread of vegetative propagules. A moderate level of genetic diversity also suggests that biological control of this weed could be successful.