We used a novel RNase cleavage assay (NIRCA) to screen for neurofibromatosis 2 (NF2) mutations in NF2 schwannomas. Mutations were found in tumors in 16 of 20 patients. Eleven patients (55%) had loss of heterozygosity or loss of one allele, indicating that the mutation was a germ-line mutation. The phenotypes of these patients were consistent with previous NF2 genotype-phenotype correlation studies: patients with nonsense mutations had severe phenotypes, whereas those with splice-site or missense mutations had milder and variable phenotypes. These results confirm the utility of NIRCA as a rapid and convenient method for screening for germ-line NF2 mutations.