Objective. To investigate the efficiency of capecitabine (CAP) plus temozolomide (TEM) in refractory pituitary adenoma after tumor resection and its impact on serum prolactin (PRL), insulin-like growth factor 1 (IGF-1), and growth hormone (GH) levels. Methods. From January 2017 to January 2020, 80 patients assessed for eligibility receiving transsphenoidal tumor resection for refractory pituitary adenoma in the Department of Neurosurgery of our hospital were recruited. They were randomly distributed at a ratio of 1 : 1 via the random number table method to receive either bromocriptine and TEM (control group) or bromocriptine plus combination chemotherapy of TEM and CAP (study group). The two groups were compared in terms of clinical efficacy and serum levels of PRL, IGF-1, and GH. Results. The objective response rate (ORR) was 87.50% and 67.50% in the study group and the control group, respectively P = 0.032 . Before treatment, two groups had similar levels of PRL, IGF-1, and GH. After treatment, PRL levels in the study group were lower than that in the control group (278.35 ± 39.25 versus 326.35 ± 42.45, P < 0.001 ). Compared with the control group, IGF-1 levels in the study group were also lower (311.78 ± 28.82 versus 364.35 ± 31.35, P < 0.001 ). The study group presented markedly lower levels of thyroid-stimulating hormone (TSH) and higher serum levels of free thyroxine-4 (FT-4) and adrenocorticotropic hormone (ACTH) versus the control group P < 0.05 . The incidence of adverse events was comparable between the study group (30.0%) and the control group (22.5%) P > 0.05 . All eligible patients had similar progression-free survival (PFS) after chemotherapy. Conclusion. For patients with refractory pituitary adenoma, the combination chemotherapy of CAP and TEM significantly improves clinical outcomes and corrects hormonal disturbances, with a good safety profile, but its long-term efficacy requires further investigation.