Novel therapeutics, including ocular gene and stem cell therapies, hold great promise to maintain and improve vision in many ocular disorders. Although the theoretical rationale and preclinical data may be encouraging, differentiation of the placebo effect from apparent benefits of these new therapies via well-designed surgical clinical trials is critical. Sham or placebo surgery has proven to be indispensable in identifying nonefficacious therapies in numerous surgical trials.1 Perhaps the most notable example is knee arthroscopy. This procedure was chosen frequently by orthopedic surgeons for osteoarthritis until multiple placebo-controlled studies found no significant difference in pain reduction or functional outcomes.2 Critics of sham surgery argue that the risks to research participants outweigh the benefits in evaluating new treatment modalities. Because constraints on the use of invasive sham surgery in ophthalmology are less well established than in other areas of medicine, how do we determine when the placebo arm is ethically justified or even permissible?