The management of refractory pituitary adenomas (RPA) presents significant challenges. This study aimed to evaluate the long-term treatment outcomes of patients with RPA managed with temozolomide (TMZ) and to identify potential biomarkers for predicting TMZ treatment response.This retrospective case series included patients with RPA who underwent transsphenoidal surgery (TSS) or craniotomy at a comprehensive medical center in China between January 2014 and December 2021.Thirty-nine patients with RPA (median age 42 years; 23 males (59%)) were treated with TMZ for a median of 9 cycles. The median follow-up was 34.4 months. Complete response (CR) was observed in 2 patients, partial response (PR) in 11 patients, stable disease (SD) in 9, progressive disease (PD) in 11, and death in 6 patients. MGMT (O6-methylguanine DNA methyltransferase) levels were significantly lower in patients with CR, PR, or SD compared to those with PD or mortality, with mean values of 24.2% and 58.1, respectively. MSH6 (MutS homologs 6) levels were significantly higher in patients with CR, PR, or SD compared to those with PD or mortality, with mean values of 64.2% and 36.9%, respectively. Patients who received concomitant TMZ and external beam radiotherapy showed a significant tumor size reduction of 178,837mm3 (p<0.001) compared to those treated with TMZ alone.TMZ demonstrates promising efficacy in eliciting tumor responses in patients with PRA. MGMT and MSH6 have emerged as potential biomarkers for predicting treatment response. Furthermore, radiation with concurrent TMZ may significantly improve outcomes in patients with RPA.Copyright © 2024. Published by Elsevier Inc.