Osteopathic manipulative medicine researchers often use sham therapy as the placebo control during clinical trials. Optimally, the sham therapy should be a hands-on procedure that is perceptually indistinguishable from osteopathic manipulative treatment, does not create an effect on its own, and is not a treatment intervention. However, the sham therapy itself may often influence the outcome. The use of cardiovascular variability (eg, beat-to-beat heart rate variability) as a surrogate for the autonomic nervous system is one objective method by which to identify such an effect. By monitoring cardiovascular variability, investigators can assess autonomic nervous system activity as a response to the sham therapy and quickly determine whether or not the selected sham therapy is a true placebo control. The authors provide evidence for assessment of beat-to-beat heart rate variability as one method for assuring objectivity of sham therapy as a placebo control in osteopathic manipulative medicine research. J Am Osteopath Assoc. 2014;114(11):860-866 doi: 10.7556/jaoa.2014.172