Theoretical perspectives hypothesize that struggling readers can increase their reading comprehension from integrating instruction in decoding and vocabulary. For older students who continue to struggle with understanding what they read in their increasingly difficult content classes, direct instruction in both areas might help improve their reading comprehension. There have been some investigations into the combined effects of combining decoding and vocabulary instruction, but the results are inconclusive. The current study used an adapted alternating treatments design (AATD) to examine the relative benefits of providing intervention in decoding plus vocabulary compared to intervention in decoding alone. For this single case design study, four participants progressed through three phases: baseline, a first instructional phase, and a second instructional phase. One instructional phase consisted of instruction on targeted words only (decoding) and the other consisted of instruction on a different set of targeted words along with their meaning (decoding + vocabulary). At the end of each session, students read several passages and answered the accompanying reading comprehension questions. The passages from Test A were aligned with decoding instruction and the passages from Test B were aligned with instruction in decoding and vocabulary. Another set of passages comprised Test C, which did not contain any instructional words. Results did not reveal a benefit from instruction in either decoding or instruction in both decoding and vocabulary on students’ reading comprehension on passages aligned with instructional content. The effects may be attributable to participants’ reading skills, which were low on a standardized test, but possibly sufficient to understand what they read on the daily assessments.