Background: In the randomized, phase III MONALEESA-2 study (NCT01958021), first-line therapy with ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor; 600 mg/day; 3-weeks-on/1-week-off) + letrozole (LET; 2.5 mg/day) in postmenopausal women with HR+, HER2– ABC significantly prolonged progression-free survival vs placebo (PBO) + LET (hazard ratio: 0.556; p = 0.00000329; Hortobagyi GN et al. N Engl J Med 2016;375:1738–48). Here we present further safety analyses from MONALEESA-2. Methods: Adverse events (AEs) were characterized per CTCAE v4.03. Analyses of key AEs included time to first event, duration (time to AE resolution), and the rate of associated dose interruptions or reductions. Results: Safety analysis included 664 patients (pts; RIB + LET: 334; PBO + LET: 330). Neutropenia was the most common all-grade (G) and G3/4 AE in the RIB + LET arm (Table); febrile neutropenia rates were low (RIB + LET arm: 1.5%) with no associated deaths. Median time to first event for G ≥2 neutropenia in the RIB + LET arm (based on neutrophil counts) was 16 days. Other common G3/4 AEs (increased by ≥5% in the RIB + LET vs PBO + LET arm) were leukopenia (21% vs 1%), elevated alanine aminotransferase (ALT; 9% vs 1%), lymphopenia (7% vs 1%), and elevated aspartate aminotransferase (AST; 6% vs 1%). Neutropenia was the most common AE leading to dose interruptions/reductions; G3/4 neutropenia led to dose interruptions in 48% vs < 1% and reductions in 30% vs 0% of pts in the RIB + LET vs PBO + LET arm. 7.5% vs 2.1% of pts (RIB + LET vs PBO + LET) discontinued due to AEs; common AEs leading to discontinuation ( > 1% pts) were elevated ALT (5% vs < 1%), elevated AST (3% vs 1%), and vomiting (2% vs 0%). Conclusions: First-line RIB + LET had a manageable safety profile in postmenopausal women with HR+, HER2– ABC. Neutropenia was the most common AE in the RIB arm, and was transient and reversible with dose modifications. Additional AE analyses will be presented. Clinical trial information: NCT01958021