Background: A significant portion of adults struggle to read at a basic level. Word reading (defined here as decoding and word recognition) appears to play a pivotal role for this population of readers; however, less is known about how word reading relates to other important semantic processes (e.g., vocabulary, sentence processing) known to account for a large portion of variance in reading comprehension. This study used the Reading Systems Framework to explore the extent that moderational and mediational relations existed between word reading and semantic processing abilities in predicting reading comprehension. Methods: Participants (N = 169) completed the Reading Inventory and Scholastic Evaluation, which consists of a series of subtests intended to measure decoding/word recognition, vocabulary, sentence processing and reading comprehension. Results: A moderated mediation model was constructed to assess the extent to which moderational and mediational relations between word reading and semantic processing were predictive of comprehension. Results suggested that word reading moderated the effect of vocabulary knowledge on comprehension among struggling adult readers. Additionally, semantic processing at the word (i.e., vocabulary) and sentence level both significantly mediated the relation between word reading and comprehension. Conclusions: Word reading moderated the relation between vocabulary and comprehension for struggling adult readers. Readers with greater word reading ability benefited most from having a higher degree of vocabulary knowledge. Vocabulary and sentence processing mediated the relation between word reading and comprehension. Thus, word reading appears to serve as an important gateway for struggling readers, and, as such, interventions targeting component skills of reading may have a limited impact on reading literacy tasks until word reading skills are developed. [This is the online version of an article published in "Journal of Research in Reading" (ISSN 0141-0423).]