Unblinded studies have demonstrated superior procedural and clinical outcomes of percutaneous coronary intervention (PCI) in focal compared with diffuse coronary artery disease. However, data from the first placebo-controlled study did not demonstrate a differential impact of disease pattern on symptom endpoints. The study sought to test the ability of pattern of coronary artery disease to predict the placebo-controlled efficacy of PCI. In the ORBITA-2 (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina-2) randomized placebo-controlled trial of angioplasty for stable angina, patients underwent prerandomization nonhyperemic pressure wire pullback assessments. Seven blinded interventional cardiologists independently reviewed each pullback trace to categorize disease patterns as focal, diffuse, or mixed. These were assigned numerical values of 1, 0, and 0.5, respectively. Overall disease pattern score was determined by the mean. A score >0.5 was considered focal and ≤0.5 was considered diffuse. Bayesian proportional odds modeling was used. A total of 245 patients with 300 target vessel pullbacks were analyzed. With adjustment for prerandomization nonhyperemic pressure ratio, PCI in focal compared with diffuse disease resulted in greater improvement in angina symptom score (OR: 1.80; 95% credible interval [CrI]: 1.48-2.18; Pr[Benefit] > 99.9%) and daily episodes of angina (OR: 1.55; 95% CrI: 1.26-1.89; Pr[Benefit] > 99.9%). Focal disease also predicted greater placebo-controlled benefit in exercise treadmill time (Pr[Interaction] > 99.9%), Canadian Cardiovascular Society class (Pr[Interaction] = 99.0%), EuroQol Group 5-Dimensions 5-Level questionnaire (Pr[Interaction] = 95.1%), and Seattle Angina Questionnaire angina frequency (Pr[Interaction] = 99.5%). There was weaker evidence of interaction between disease pattern and the placebo-controlled impact of PCI on improvement in dobutamine stress echocardiography score (Pr[Interaction] = 83%). In focal disease, PCI resulted in greater placebo-controlled improvement of symptoms compared with diffuse disease. Physiological patterns of disease may be useful to guide treatment decision making with PCI for symptom relief.