Objective: The objective of this study was to provide guidance on the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to determine certainty in estimates of association between prognostic factors and future outcomes. Study Design and Setting: We developed our guidance through an iterative process that involved review of published systematic reviews and meta-analyses of prognostic factors, consultation with members, feedback, presentation, and discussion at the GRADE Working Group meetings. Results: For questions of prognosis, a body of observational evidence (potentially including patients enrolled in randomized controlled trials) begins as high certainty in the evidence. The five domains of GRADE for rating down certainty in the evidence, that is, risk of bias, imprecision, inconsistency, indirectness, and publication bias, as well as the domains for rating up, also apply to estimates of associations between prognostic factors and outcomes. One should determine if their ratings do not consider (noncontextualized) or consider (contextualized) the clinical context as this will may result in variable judgments on certainty of the evidence. Conclusions: The same principles GRADE proposed for bodies of evidence addressing treatment and overall prognosis work well in assessing individual prognostic factors, both in noncontextualized and contextualized settings.