In this study, we examined 5th grade students’ levels of vocabulary knowledge and syntactic awareness relative to their reading comprehension performance. The aim was to explore the contributions of vocabulary and syntactic awareness as potential sources of reading comprehension difficulty for these readers. Overall, we found that both vocabulary knowledge and syntactic awareness contributed in significant yet unique ways to students’ reading comprehension performance. Students who showed weaknesses in vocabulary and syntax also performed poorly on measures of reading comprehension. Additionally, we found that syntactic awareness explained a small amount of additional variance in reading comprehension beyond what was explained by vocabulary. The implications of these findings are discussed in light of research and practice addressing the relationships among syntax, vocabulary, and reading comprehension for more and less skilled readers.