Background: HIV/AIDS remains a significant public health challenge in Kenya, particularly in high-burden regions like Kisumu County. While Pre-exposure Prophylaxis (PrEP) is a highly effective prevention tool, its success is limited by barriers to both initial initiation and long-term retention. This study aimed to identify the socio-demographic, economic, and behavioural predictors of PrEP uptake among naïve individuals and continuity among experienced users. Methods: An analytical mixed-methods cross-sectional study was conducted in January 2024 across four sub-counties in Kisumu. A total of 435 participants (358 PrEP-naïve and 77 PrEP-experienced) were recruited from high-volume health facilities via systematic random sampling. Quantitative data from structured questionnaires were analyzed using STATA 17, while qualitative data from twelve key informant interviews with healthcare providers were analyzed thematically using NVivo 12. Results: Among PrEP-naïve respondents, 88.12% were willing to initiate PrEP. Significant positive predictors of uptake included being a student (OR=3.882, p<0.001), while rural residence (OR=0.432, p=0.005) and primary education (OR=0.511, p=0.018) were significant barriers. Among experienced users, 46.15% had discontinued PrEP. Predictors of continuity included marital status, where never-married individuals had 77% lower odds of staying on PrEP (OR=0.227, p=0.003). Key reasons for discontinuation were low HIV risk perception (61.11%), side effects, and relocation. Conclusion: High initial willingness is undermined by structural and socio-behavioural barriers to continuity. HIV prevention programs should prioritize partner-based support, side-effect management, and flexible delivery models to improve retention in high-burden counties.