Abstract Purpose Pituitary diseases severely affect patients’ health-related quality of life (HRQoL). The most frequently used generic HRQoL questionnaire is the Short Form-36 (SF-36). The shorter 12-item version (SF-12) can improve efficiency of patient monitoring. This study aimed to determine whether SF-12 can replace SF-36 in pituitary care. Methods In a longitudinal cohort study (August 2016 to December 2018) among 103 endoscopically operated adult pituitary tumor patients, physical and mental component scores (PCS and MCS) of SF-36 and SF-12 were measured preoperatively, and 6 weeks and 6 months postoperatively. Chronic care was assessed with a cross-sectional study (N = 431). Mean differences and agreement between SF-36 and SF-12 change in scores (preoperative vs. 6 months) were assessed with intraclass correlation coefficients (ICC) and limits of agreement, depicting 95% of individual patients. Results In the longitudinal study, mean differences between change in SF-36 and SF-12 scores were 1.4 (PCS) and 0.4 (MCS) with fair agreement for PCS (ICC = 0.546) and substantial agreement for MCS (ICC = 0.931). For 95% of individual patients, the difference between change in SF-36 and SF-12 scores varied between −14.0 and 16.9 for PCS and between −7.8 and 8.7 for MCS. Cross-sectional results showed fair agreement for PCS (ICC = 0.597) and substantial agreement for MCS (ICC = 0.943). Conclusions On a group level, SF-12 can reliably reproduce MCS in pituitary patients, although PCS is less well correlated. However, individual differences between SF-36 and SF-12 can be large. For pituitary diseases, alternative strategies are needed for concise, but comprehensive patient-reported outcome measurement.