Objectives: To investigate characteristics of health-related quality of life and evaluate the association between health-related quality of life (HRQoL) and hearing among different types of chronic middle ear diseases (CMED). Design: Prospective longitudinal cohort study. Setting: Tertiary referral centre. Participants: Adult patients undergoing surgical treatment for CMED. Main outcomes measures: Pure-tone audiometry, Zurich Chronic Middle Ear Inventory (ZCMEI-21). Results: A total of 108 patients (55 females, 53 males; mean age 51.0 years [SD 15.9]) were included. CMED included COM with cholesteatoma (epitympanic [n = 39]; pars tensa [n = 7]), persistent mastoid cavity (with recurrent cholesteatoma; n = 15; without recurrent cholesteatoma, n = 10), COM without cholesteatoma (n = 22), revision ossiculoplasty for hearing restoration (n = 14), and postinflammatory meatal fibrosis (n = 1). No significant differences between pre- and postoperative air conduction pure-tone average was observed in any type of CMED. Preoperatively, mean ZCMEI-21 score showed statistically significant differences among different types of CMED (p = 0.007) with persistent mastoid cavity without cholesteatoma exhibiting the highest mean ZCMEI-21 score (34.1, SD 7.7) indicating a poor HRQoL. At a mean follow-up period of 183 days, no statistically significant differences in ZCMEI-21 scores among different types of CMED were observed (p = 0.67). Conclusion: This study objectifies differences in HRQoL among different types of CMED. In types of CMED with indication for functional surgery only, such as persistent mastoid cavity without cholesteatoma or ossiculoplasty, the worst HRQoL was observed. Yet, in these types of CMED, HRQoL guides decision for treatment. Moreover, differences in HRQoL among different types of CMED are not closely associated with hearing, but largely depend on other symptoms, such as tinnitus, discharge or vertigo.