Purpose: Hypopituitarism is a rare disorder with significant morbidity. To study the evidence on the association of premature mortality and hypopituitarism. Methods: A comprehensive search of multiple databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was conducted through August, 2015. Eligible studies that evaluated patients with hypopituitarism and reported mortality estimates were selected following a predefined protocol. Reviewers, independently and in duplicate, extracted data and assessed the risk of bias. Results: We included 12 studies (published 1996–2015) that reported on 23,515 patients. Compared to the general population, hypopituitarism was associated with an overall excess mortality (weighted SMR of 1.55; 95 % CI 1.14−2.11), I2 = 97.8 %, P = 0.000. Risk factors for increased mortality included younger age at diagnosis, female gender, diagnosis of craniopharyngioma, radiation therapy, transcranial surgery, diabetes insipidus and hypogonadism. Conclusion: Hypopituitarism may be associated with premature mortality in adults. Risk is particularly higher in women and those diagnosed at a younger age.