Purpose Different types of chronic middle ear disease (CMED) present with differing severity of single symptoms, such as discharge, vertigo or hearing loss, which impair health-related quality of life (HRQoL). Here, we aimed to (i) investigate characteristics of HRQoL and (ii) evaluate the association between HRQoL and hearing among different types of CMED. Methods In this prospective longitudinal cohort study, we included adult patients undergoing surgical treatment for CMED. Primary outcomes included HRQoL assessed by the Zurich Chronic Middle Ear Inventory (ZCMEI-21) and hearing assessed by pure-tone audiometry. Results In the included 108 patients (51% females), CMED were chronic otitis media (COM) with ( n  = 46) or without ( n  = 22) cholesteatoma, persistent mastoid cavity (with n  = 15 or without n  = 10 recurrent cholesteatoma), revision ossiculoplasty for hearing restoration ( n  = 14), and postinflammatory meatal fibrosis ( n  = 1). Preoperatively, the 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 score (34.1, SD 7.7) indicating poor HRQoL. At a mean follow-up period of 183 days, no statistically significant differences in the 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 patients with indication for functional surgery only, e.g., persistent mastoid cavity without cholesteatoma, 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 were not closely associated with hearing, but largely depended on other symptoms, such as discharge or vertigo.