Background: We evaluated complex pre-exposure prophylaxis (PrEP) situations linked to kidney issues in a cohort of on-demand and daily PrEP users. Setting: We conducted a single-center retrospective cohort study in France including all PrEP users who received a tenofovir disoproxil (TD)--emtricitabine (FTC) prescription between January 1, 2012 and December 31, 2019 with at least 1 creatinine measurement available before and after PrEP initiation. Methods: A complex kidney situation (CKS) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73m² on 2 consecutive measurements. We estimated the incidence of this event, described case management, and identified associated factors using a Cox model. Results: Three thousand one hundred and fourteen individuals were included in this study. Almost all were men (99%) with a median age of 35 years, 25% had an eGFR <90 mL/minute/1.73m² at baseline, and 65% used on-demand PrEP. Nine users (0.29%) had a CKS at baseline; 8/9 initiated on-demand PrEP without renal function worsening after a median (interquartile range [IQR]) follow-up time of 14 months (7-31). Thirteen cases of CKS occurred during the follow-up for a 0.25 per 100 person-years incidence (95% confidence interval [CI]: [0.14; 0.45]). On-demand PrEP was used in 7/13 participants with no further episode of confirmed eGFR <60 mL/ minute/1.73m² after a 17-month median follow-up (IQR 4-18). CKS was associated with an age ≥50 years (hazard ratio [HR] 13, 95% CI: [4-39]) or with a baseline eGFR <90 mL/minute/1.73m² (HR 34, 95% CI: [4-261]). 9/22 CKS were linked to high-protein intake for weight training. Conclusions: CKS were rare in our cohort. On-demand PrEP did not result in subsequent renal function worsening in these few situations. [ABSTRACT FROM AUTHOR]