Background Chronic Obstructive Pulmonary Disease (COPD) is one of the prominent cause of mortality worldwide. Nowadays, the level of medication adherence in COPD patients is very low, which reduces the clinical therapeutic effects. The purpose of the present study is to investigate the relationship between medication adherence and Health-Related Quality of Life (HRQoL) in COPD patients referred to the pulmonologist’s office. Methods This observational study was performed on 100 COPD outpatient cases. Each patient was interviewed to answer questionnaires regarding demographic and clinical information. To assess quality of life, health status, and severity of dyspnea, the St George’s Respiratory Questionnaire - COPD-Specific Version (SGRQ-C), COPD Assessment Test (CAT), and Modified British Medical Research Council (mMRC) questionnaires were used, respectively. Persian version of the Morisky Medication Adherence Scale (MMAS-8-Item) was used to measure medication adherence. To determine the adherence predictors, an ordinal logistic regression analysis was performed. Results Out of 100 patients with mean (±SD) age of 61.35 (±10.79) years, 74% had medium and high medication adherence. In the final ordinal logistic model, quality of life, health status, and education level found to have positive effect on medication adherence while polypharmacy had negative effect. We did not find any significant association between age, gender, Body Mass Index (BMI), and other variables with medication adherence. Conclusions Patients with high quality of life are more adherent to their medications. Furthermore, patients who have polypharmacy, tend to have less adherence to their medications.