<p>Frailty is associated with incident cognitive impairment in patients receiving hemodialysis; however, this association in patients with non-dialysis CKD remains unknown. In addition, recent evidence points to a sex-frailty paradox in cognitive impairment, a phenomenon that has not yet been examined in non-dialysis CKD. We aimed to evaluate the association between frailty and incident cognitive impairment in the Chronic Renal Insufficiency Cohort study participants and to explore whether this association differs by sex. The predictor was baseline frailty and the outcome was incident cognitive impairment (defined as a decline in the Modified Mini-Mental State Examination [3MS] score by more than 1 standard deviation below the cohort mean). Cox proportional hazards models were used to examine the association between frailty and cognitive impairment in the entire cohort and stratified by sex. A total of 1,370 patients (41% women; 64 ± 9&#xa0;years; baseline eGFR of 59 ± 13 mL/min/1.73 m²) with a baseline 3MS score of 92.6 ± 5.0 were included. At baseline, frailty was more prevalent in women than men (16% vs. 9%), while men had a higher incidence of cognitive impairment than women (3.2 vs. 1.9 events/100 person-years). Over a median follow-up of 5.5&#xa0;years (IQR, 4.8–6.1), frail men had 2.09-fold higher risk of cognitive impairment vs. non-frail men (hazard ratio [HR] = 2.09 [95% CI, 1.003 to 4.373]) in the fully adjusted model, whereas no association was observed in women. These results suggest frailty may be an independent risk factor for incident cognitive impairment in men with non-dialysis CKD, but not in women.</p>