Increasing evidence of impaired pituitary function in many subjects with primary empty sella (PES) has been reported. We conducted a retrospective analysis of our patients with PES, in order to ascertain presenting symptoms and endocrine status on diagnosis and during follow-up. Magnetic resonance imaging (MRI) of the pituitary leading to the diagnosis of PES was performed in 8 patients (5 F and 3 M, age: 60.1 ± 3.3 years, M ± SE; group 1) after the diagnosis of global anterior hypopituitarism (H), and in 20 patients (F, age 56.9 ± 2.2 years, group 2) for other clinical reasons. Baseline determinations of pituitary and target gland hormones and of IGF-I were performed. GH response to GHRH plus arginine stimulation was also evaluated. Ten age- and BMI-matched subjects (7 F, 3 M, age: 53.0 ± 4.0 years) with normal pituitary function served as controls (C). In group 1, the presenting symptoms leading to the diagnosis of H were consciousness disturbances, hyponatremia and chronic fatigue. The GH response to stimulation was absent (peak:1.0 ± 0.3 ng/ml) and IGF-I levels (60.1 ± 9.3 ng/ml) were significantly lower (p<0.001) than in C and group 2 PES patients. Among group 2 PES patients, the main presenting symptoms were headache and visual alterations. Baseline hormone levels proved normal in 17 subjects, while slight hyperprolactinemia was observed in 2 and hypogonadotropic hypogonadism in one. The GH response to stimulation (12.9 ± 3.4 ng/ml) and IGF-I levels (141.7 ± 12.0 ng/ml) were lower (p<0.05) than in C (GH: 33.4 ± 8.8 ng/ml, IGF-I: 193.1 ± 20.3 ng/ml). PES is a heterogeneous condition that ranges from hypopituitarism to various degrees of isolated GH deficiency, and which needs careful endocrine assessment, treatment and follow-up.