A Summary This retrospective, observational study assessed 2year persistence and compliance by treatment, route of administration, and dosing frequency in postmenopausal women initiating a new osteoporosis therapy. Two-year persistence and compliance rates were higher in women receiving injectables compared with oral agents. Purpose This study extends previous studies limited to 1-year follow-up by examining persistence with osteoporosis therapies over a 2-year period and compares short-and long-term trends in persistence and compliance among postmenopausal women with commercial or Medicare supplemental insurance in the USA. Methods This retrospective, observational cohort study enrolled women >= 50 years newly initiating osteoporosis therapy between January 1 and December 31, 2012 (i.e., the index date), with continuous enrollment >= 14 months before and >= 24 months after their index date. Persistence (continuous therapy without a >60-day gap) and compliance with the index therapy were evaluated at 2 years of follow-up. Multivariable logistic regression was used to compare the odds of persistence and compliance across treatment and dosing regimens. Results This study included 43,543 patients with mean (standard deviation) age 65 (10) years. At 2 years of follow-up, persistence and compliance were higher for patients treated with injectable agents (ranging from 34 to 41%, excluding an every-3-month injection) than those treated with oral agents (ranging from 20 to 31%). Additionally, patients initiating oral bisphosphonates (except risedronate once daily), raloxifene (daily), or zoledronic acid (annually) had significantly lower odds of persistence compared with denosumab (every 6 months). Conclusions Patients initiating injectable therapies had greater persistence and compliance at 2 years than those initiating oral therapies. Patients initiating an every-6-month injection had significantly higher persistence compared with those initiating more frequently dosed (e.g., daily and weekly) oral or injectable agents.