Our previous investigation2 suggested that masking of patient participants via a sham intervention may not be necessary when visual acuity outcomes are evaluated following measurements made according to a standard protocol, particularly when the visual acuity examiner is masked to random assignment. The current analysis suggests that masking of patient participants via a sham or placebo intervention may be unnecessary when patient-reported outcomes based on the NEI-VFQ and administered by interviewers masked to treatment assignment are of interest. Much more extensive investigation in larger studies and, ideally, in studies of different designs is necessary to delineate situations in which no-treatment controls may be sufficient. We encourage other researchers to undertake similar analyses using data sets from other pairs of randomized trials in which similar patients are enrolled but the types of controls differ. Because treatments currently are available that usually delay, prevent, or reverse visual acuity loss resulting from subfoveal CNV in AMD, it is unlikely that there will be an opportunity to make a randomized comparison in future trials of treatments for such patients. However, we continue to encourage sponsors and designers of clinical trials of new therapeutic and preventive interventions for ophthalmologic conditions for which no effective treatment is available to consider a design in which patients assigned to the control arm are randomized between sham and no treatment, regardless of whether visual acuity, patient-reported outcomes, or other outcomes are assessed. Evidence from multiple trials with internally randomized control arms would help to delineate the circumstances that require sham controls to minimize bias in estimating treatment effects, along with the risk, cost, deception, and inconvenience they entail, and those in which no-treatment controls are acceptable. Until such a body of evidence is available to inform decisions regarding selection of the control by researchers and by regulatory agencies that approve clinical trial protocols and new interventions, we encourage designers of clinical trials to consider all scientific, ethical, logistic, and financial aspects of masking of clinical trial participants before deciding whether a sham control or a no-treatment control, together with masked outcome assessment and other protections against bias, is the better method to achieve trial objectives.