Background: In the MONALEESA-2 trial, ribociclib + letrozole significantly improved progression-free survival and showed higher overall response rates vs placebo + letrozole in hormone receptor–positive, HER2– advanced breast cancer. Here, we present key patient-reported outcomes including health-related quality of life (HRQoL). Methods: Six hundred sixty-eight patients were randomized (n = 334 for each treatment group). Patient-reported outcomes were evaluated during treatment and at progression using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-BR23. Changes from baseline in all subscales were analyzed using a linear mixed-effects model, and time to 10% deterioration was compared between treatment arms using the stratified log-rank test. Results: Questionnaire adherence 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, 0.944; 95% confidence interval, 0.720–1.237). No statistically or clinically relevant differences were observed for key symptoms using EORTC QLQ-C30 including fatigue, nausea, and vomiting. There was clinically relevant improvement ( > 5 points) in pain from baseline to post baseline (through cycle 15) in the ribociclib + letrozole arm, but only mild improvement (≤5 points) in the placebo + letrozole arm. Conclusions: Ribociclib + letrozole maintained HRQoL, and a numerical trend favoring ribociclib + letrozole was observed for pain reduction and delay. Clinical trial information: NCT01958021