Abstract Summary This retrospective study reports 81% long-term (> 3 years) adherence to and 77% persistence with zoledronic acid (ZA) treatment in osteoporosis patients, with ZA being costfree for patients. Eight percent of patients discontinued treatment because of adverse events (AEs), with a tendency of higher discontinuation rate in older patients. Purpose This study investigated (1) long-term adherence to and persistence with ZA treatment in a real-world setting, (2) extent to which an adverse reaction to ZA impacted on adherence and persistence, and (3) whether there were sex or age differences in patients that had early treatment termination (ETT) due to AEs and those who adhered to the regimen. Methods All patients treated with ZA at the Endocrinology Department at Linköping University Hospital, Linköping, Sweden between 2012 and 2017 were included. ETT was defined as < 3 ZA infusions, which was confirmed from patients’ medical records. Results A total of 414 patients were treated with ZA, with 81% receiving > 3 ZA infusions. Three-year persistence was 77% for a treatment window of 365 days ± 90 days (75% with 365 days ± 60 days window). The most common reason for ETT was AEs (8%), followed by medical conditions (5%), biological aging (3%), and other (e.g., lost to follow-up [3%]). Most patients who discontinued treatment because of AEs reported symptoms of acute-phase reaction, and tended to be older than those who adhered to treatment (74 ± 9 vs 70 ± 13 years, p = 0.064). There was no difference in sex ratio between the 2 groups (85% vs 90% females, p = 0.367). Conclusion Rates of long-term adherence to and persistence with ZA treatment were high with a pre-scheduled 3-year treatment regimen in the tax-financed Swedish healthcare system. AEs—mainly acute-phase reaction—were the most common reason for ETT, occurring in nearly 1 out of 10 patients.