Objective: Risk difference (RD) is often estimated from relative association measures generated by meta-analysis and a particular group's baseline risk. We describe a problematic situation in using this approach. Study Design and Setting: We encountered a meta-analysis in which a confidence interval (CI) of relative risk (RR) overlapped 1.0; the point estimate favored treatment A, but when we used RR and median baseline risk to calculate a CI for RD, a greater portion of the CI favored treatment B (a result that some may find counterintuitive). We then calculated 10 different RDs from recently published meta-analyses in outcomes in which CIs of RR crossed 1.0 using three methods: estimation from RR, estimation from the odds ratio, and pooling RDs across trials. Results: When RD is estimated from relative measures, the counterintuitive result occurred in 2 of 10 instances. This discordance of interpretation is because of the logarithmic transformation that makes CIs of relative measures asymmetric around their point estimates. Conclusion: When RD is estimated from relative association measures that are nonsignificant and this counterintuitive situation occurs, it may be more appropriate to pool RD across studies. Pooling is particularly valid when baseline risks across studies are homogeneous. © 2009 Elsevier Inc. All rights reserved.