Instrumental variable analysis is an increasingly popular method in comparative effectiveness research (CER). In theory, the instrument controls for unobserved and observed patient characteristics that affect the outcome. However, the results of instrumental variable analyses in observational settings may be biased if the instrument and outcome are related through an unadjusted third variable: an "instrument-outcome confounder." The authors identified published CER studies that used instrumental variable analysis and searched the literature for potential confounders of the most common instrument-outcome pairs. Of the 187 studies identified, 114 used 1 or more of the 4 most common instrument categories: distance to facility, regional variation, facility variation, and physician variation. Of these, 65 used mortality as an outcome. Potential unadjusted instrument-outcome confounders were observed in all studies, including patient race, socioeconomic status, clinical risk factors, health status, and urban or rural residency; facility and procedure volume; and co-occurring treatments. Only 4 (6%) instrumental variable CER studies considered potential instrument-outcome confounders outside the study data. Many effect estimates may be biased by the failure to adjust for instrument-outcome confounding. The authors caution against overreliance on instrumental variable studies for CER.