The root hemiparasite Striga hermonthica is a serious constraint to grain production of economically important cereals in sub-Saharan Africa. Breeding for parasite resistance in cereals is widely recognized as the most sustainable form of long-term control; however, advances have been limited due to a lack of germplasm demonstrating post-attachment Striga resistance. Over 50 rice cultivars (Oryza sativa subspecies japonica and indica) were screened for post-attachment resistance to Striga hermonthica; all were susceptible with the exception of one cultivar, Nipponbare (japonica type), which was resistant. To our knowledge, this is the first report of such resistance in a cereal host to this devastating parasite. The phenotype of the resistance differed from that reported for resistance in cowpea to S. gesnerioides. Striga hermonthica was able to penetrate the root cortex of Nipponbare but was unable to form parasite–host xylem–xylem connections. Without vascular continuity with the host the parasite is unable to tap into host water, nutrients or developmental cues necessary for its further development, and it dies. To identify the genomic regions contributing to this resistance a mapping population of backcross inbred lines between the resistant (Nipponbare) and a susceptible (Kasalath) parent were evaluated for resistance to S. hermonthica. Composite interval mapping located putative quantitative trait loci (QTLs) explaining 31% of the overall phenotypic variance; a second, independent screen confirmed five of these QTL. Unsurprisingly the Nipponbare allele conferred greater resistance than the Kasalath allele at four of the five QTLs. However, a QTL of large effect on chromosome 4 showed a direction in the opposite effect; the Kasalath allele was more resistant than the Nipponbare allele. In practical terms this discovery is exciting; introgression of the Kasalath allele into a Nipponbare background would result in a phenotype even more resistant than Nipponbare. The distribution of S. hermonthica resistance in the mapping population is consistent with a polygenic mode of inheritance. To determine whether resistance was due to a few genes of large effect or to many genes of small effect we examined QTL magnitude as an effect size relative to the phenotypic variance observed in the parental races. Here, resistance in both Nipponbare and Kasalath had a standard deviation ~0.08, while the effects of an allelic substitution at the QTL ranged from 0.036 to 0.075. Thus under the usual definition of an allelic substitution that alters phenotype by at least 0.5 of a phenotypic standard deviation, these QTL should be considered major genes. A key challenge in the future is to finely map, and ultimately to identify the causative mutations or quantitative trait nucleotides that are responsible for the S. hermonthica QTL and to develop molecular markers for use in marker-assisted breeding programs.