The study examined the interaction effects of prior knowledge and hypertexts structure (network vs. hierarchy) on comprehension. Comprehension was investigated analyzing jointly three dependent variables: comprehension outcomes, coherence of the reading sequences and feelings of disorientation. The results supported most of the assumptions showing an interaction effect on each measure. For low prior knowledge readers, a hierarchical structure improved comprehension performance, helped them to follow coherent reading sequences and reduced their feelings of disorientation. For high prior knowledge readers, comprehension performance and feelings of disorientation were not affected by the type of structure. Moreover, prior knowledge was a relevant resource to cope with the cognitive requirements of reading non-linear texts. In the network condition, prior knowledge supported better comprehension, led the readers to follow more coherent reading sequences and limited their feelings of disorientation. The discussion dealt with processes based on prior knowledge involved in hypertext comprehension, and stressed the need for conducting further investigations on the nature of the on-line inferences and on relations between performance, navigation and disorientation.