Objective MGMT expression in brain and pituitary tumors has been correlated with temozolomide treatment. Few medical therapies are available in patients with Nelson Syndrome. The aim of the present study was to assess immunohistochemical expression of MGMT in ACTH‐secreting pituitary adenomas in patients with Nelson Syndrome. Methods Our material consisted of specimens from ACTH‐secreting pituitary adenomas from patients with Nelson Syndrome. Immunohistochemical staining for MGMT was performed using the streptavidin‐biotin‐peroxidase complex method. MGMT immunoreactivity was assessed microscopically and recorded as an estimated percentage of nuclear MGMT immunopositivity. (0=none, 1=<10%, 3=<50%, 4=>50%) Results Male:Female ratio was 3:5, with average patient age being 62 (range 57–66). Five of the eight specimens (65%) exhibited no MGMT immunoreactivity, with two out of eight cases (25%) showing slight MGMT immunopositivity and one out of eight cases (12%) demonstrating moderate MGMT immunopositivity (<25%). Conclusions Temozolomide therapy may be useful in patients with Nelson Syndrome. Absent or low MGMT staining in brain and other neoplasms has been shown to correlate with successful treatment with temozolomide, and recent reports assessing aggressive pituitary adenomas suggest similar outcome.