The microtubule-associated protein tau is the main component of the paired helical filaments (PHFs) of Alzheimer's disease, the most common senile dementia. To understand the origin of tau's abnormal assembly we have studied the influence of other cytosolic components. Here we report that PHF assembly is strongly enhanced by RNA. The RNA-induced assembly of PHFs is dependent on the formation of intermolecular disulfide bridges involving Cys322 in the third repeat of tau, and it includes the dimerization of tau as an early intermediate. Three-repeat constructs polymerize most efficiently, two repeat constructs are the minimum number required for assembly, and even all six full-length isoforms of tau can be induced to form PHFs by RNA.