OBJECTIVES: Clinical evidence supports the use of everolimus-based therapy (EVE) and of fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) whose disease progressed on non-steroidal aromatase inhibitor (NSAI). However, direct evidence was lacking on the comparative effectiveness of these agents. This study compared progression-free survival (PFS) between EVE and FUL in a real-world setting. METHODS: This retrospective chart review examined postmenopausal HR+/HER2- mBC patients in community-based oncology practices who received EVE or FUL (index therapy) for mBC as first-line, second-line, or third- or later-lines after NSAI. PFS from index therapy initiation was assessed and compared using Kaplan-Meier analysis and a Cox proportional hazards model adjusting for index therapy line and characteristics at mBC diagnosis and index therapy initiation. RESULTS: A total of 192 and 156 patients received EVE or FUL, respectively, in a quota-based sample. EVE patients were less likely to have bone metastases, more likely to have visceral metastases or to have received prior chemotherapy for mBC, and had a shorter duration from initiation of last adjuvant endocrine therapy to mBC diagnosis. No significant PFS difference was observed in the unadjusted analysis. After adjusting for baseline characteristics, EVE patients had significantly longer PFS compared to FUL patients (hazard ratio [HR] = 0.71, 95% CI [0.51, 0.99], p = 0.045). When stratified by treatment line, second-line and third- or later-line EVE patients had significantly longer PFS (second-line: HR = 0.52, 95% CI [0.29, 0.91], p = 0.023; third- or later-lines: HR = 0.48, 95% CI [0.24, 0.93], p= 0.031) than FUL patients of the same treatment line. CONCLUSIONS: Among postmenopausal women with HR+/HER2- mBC who progressed on NSAI, the use of EVE was associated with better PFS, particularly on second-, third- and later-lines of treatment.