To minimize bias, clinical practice guidelines (CPG) for managing patients with multiple conditions should be informed by well-planned syntheses of the totality of the relevant evidence by means of systematic reviews and meta-analyses. However, deficiencies along the entire evidentiary pathway hinder the development of evidence-based CPGs. Published reports of trials and observational studies often do not provide usable data on treatment effect heterogeneity, perhaps because their design, analysis and presentation is seldom geared towards informing on how multimorbidity modifies the effect of treatments. Systematic reviews and meta-analyses inherit all the limitations of their building blocks and introduce additional of their own, including selection biases at the level of the included studies, ecological biases, and analytical challenges. To generate recommendations to help negotiate some of the challenges in synthesizing the primary literature, so that the results of the evidence synthesis is applicable to the care of those with multiple conditions. Informal group process. We have built upon established general guidance, and provide additional recommendations specific to systematic reviews that could improve the CPGs for multimorbid patients. We suggest that following the additional recommendations is good practice, but acknowledge that not all proposed recommendations are of equal importance, validity and feasibility, and that further work is needed to test and refine the recommendations.