The role of obesity in fracture risk remains uncertain and inconclusive in postmenopausal women. Our study aimed to assess the relationship between obesity and risk of major osteoporotic fracture (MOF;​ ie, a clinical fracture of upper arm or shoulder, hip, spine, or wrist) in postmenopausal women, after taking frailty into consideration. We used the data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 5‐year Hamilton cohort for this study. Frailty was measured by a frailty index (FI) of deficit accumulation at baseline. We incorporated an interaction term (obesity × FI) in the Cox proportional hazards regression model. We included 3985 women (mean age 69.4 years) for analyses, among which 29% were obese (n = 1118). There were 200 (5.02%) MOF events documented during follow‐up:​ 48 (4.29%) in obese women and 152 (5.65%) in the nonobese group. Significant relationships between obesity, frailty, and MOF risk were found:​ hazard ratio (HR) = 0.72 (95% confidence interval [CI] 0.67–0.78) for those with an FI of zero regarding MOF risk among obese women, and HR = 1.34 (95% CI 1.11–1.62) per SD increase in the FI among nonobese women. The interaction term was also significant:​ HR = 1.16 (95% CI 1.02–1.34) per SD increase in the FI among obese women. Increased HRs were found with higher FIs regarding the relationship between obesity and MOF risk, indicating increasing frailty attenuated the protective effect of obesity. For example, although the HR for obesity and MOF risk among those who were not frail (FI = 0) was 0.72 (95% CI 0.67–0.78), among those who were very frail (FI = 0.70), the HR was 0.91 (95% CI 0.85–0.98). To conclude, after taking frailty into consideration, obesity was significantly associated with decreased risk of MOF in postmenopausal women among those who were not frail;​ however, increasing frailty attenuated this protective effect of obesity. Evaluating frailty status may aid in understanding of the complex relationship between obesity and fracture risk.