A systematic review was conducted to assess the available evidence for the effectiveness of interventions aiming to improve the comprehensibility of health-related documents in older adults (≥50) with different levels of health literacy. Seven databases were searched (2005 forward), and references in relevant reviews were checked. The selection procedure was conducted by 2 independent reviewers. Data extraction and assessment of the quality of the resulting studies were conducted by 1 reviewer and checked for accuracy by a 2nd reviewer. A total of 38 intervention studies had a study population of older adults (n = 35) or made an explicit comparison between age groups, including older adults (n = 3). Inconsistent evidence was found for the importance of design features to enhance the comprehensibility of health-related documents. Only for narratives and multiple-feature revisions (e.g., combining revisions in textual and visual characteristics) did the included studies provide evidence that they may be effective for older adults. Using narrative formats and/or multiple-feature revisions of health-related documents seem to be promising strategies for enhancing the comprehensibility of health-related documents for older adults. The lack of consistent evidence for effective interventions stresses the importance of (a) replication and (b) the use of standardized research methodologies.