Background: Assessment of quality of life in patients with stable angina and normal gated single-photon emission computed tomography myocardial perfusion imaging (MPI) remains undefined. Symptom evolution in response to imaging findings has important implications on further diagnostic testing and therapeutic interventions. Methods: Prospective cohort study was conducted at the University of Alabama at Birmingham enrolling 87 adult participants with stable chest pain from the emergency room, hospital setting, and outpatient clinics. Patients underwent MPI with technetium-99m Sestamibi and had a normal study. Participants filled out Seattle Angina Questionnaires initially and at 3-month follow-up. Results: Among the 87 participants (60 ± 12 years; 40% African American, 70% women, 29% diabetes), the mean score increased by an absolute value of 14.2 [95% CI 10.4–18.7, P <.001] in physical limitation, 23.2 [95% CI 17.1–29.4, P <.001] in angina stability, 10.9 [95% CI 7.6–14.1, P <.001] in angina frequency, and 20.6 [95% CI 16.5–24.7, P <.001] in disease perception. There was no significant change in the mean score of treatment satisfaction [− 1.4, 95% CI − 4.7 to 1.8, P =.38]. At 3-month follow-up, 28 of 87 participants (32%) were angina free. Conclusions: Patients with stable chest pain and normal MPI experience significant improvement in functional status, quality of life, and disease perception in the short term.