Background: In the MONALEESA-2 trial, ribociclib + letrozole significantly improved progression-free survival (PFS) and showed higher overall response rates vs letrozole alone in HR+, HER2– ABC. To place these clinical results in the context of patient experience, here we present key patient-reported outcomes (PROs) including HRQoL. Methods: 668 patients were randomized (1:1); 334 each to the ribociclib + letrozole and placebo + letrozole arms. PROs were evaluated during treatment and at progression using the EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L questionnaires. Changes from baseline in all subscales were analyzed using a linear mixed-effect model and time to 10% deterioration was compared between treatment arms using the stratified log-rank test. Results: Questionnaire compliance rates were high (≥90%). During treatment, HRQoL (global health status/QoL score) was maintained and similar in both treatment arms. At progression/end of treatment, HRQoL worsened numerically in both arms. Time to definitive 10% deterioration of HRQoL was similar between treatment groups, slightly favoring the ribociclib + letrozole arm (hazard ratio: 0.89; 95% confidence interval: 0.67–1.18). No statistically or clinically relevant differences were observed for key symptoms using EORTC QLQ-C30 including fatigue, nausea, and vomiting. There was a clinically relevant ( > 5 points) improvement in pain from baseline to post-baseline (up to Cycle 15) in the ribociclib + letrozole arm while there was only mild improvement ( < 5 points) observed in the placebo + letrozole arm. Conclusions: In addition to significantly improving PFS, ribociclib + letrozole maintains HRQoL when compared with letrozole + placebo. A numerical trend was observed favoring ribociclib + letrozole for pain reduction. Clinical trial information: NCT01958021