Background: The risk factors for skin injuries remain poorly understood in cancer patients with peripherally inserted central catheters (PICC). We herein aimed at exploring the effect of clinical factors on the risk of PICC-related skin injuries. Methods: We included 1245 cancer patients with PICC from 16 hospitals in Suzhou, China. The study outcome was in-hospital skin injuries, including contact dermatitis, skin (epidermal) stripping, tension injury, allergic dermatitis, skin tear, maceration, folliculitis, and pressure injury. Results: During hospitalization, 274 patients (22.0%) developed skin injuries after prolonged use of an indwelling catheter. Univariable logistic regression analysis identified several risk factors for PICC-related skin injuries; multivariable logistic regression analysis showed that the following factors independently and significantly ( p < 0.05) associated with the risk of PICC-related skin injuries: body mass index (BMI, >25 kg/m² versus <18.5 kg/m²: odds ratio (OR), 1.79; 95% confidence interval (CI), 1.03–3.11), skin condition (humid vs normal: OR, 2.96; 95% CI, 1.62–5.43), skin indentation (OR, 4.67; 95% CI, 3.31–6.58), allergic history (OR, 2.11; 95% CI, 1.21–3.66), history of dermatitis (OR, 3.05; 95% CI, 1.00–9.28), history of eczema (OR, 3.36; 95% CI, 1.20–9.43), catheter insertion site (under elbow vs. upper arm: OR, 3.32; 95% CI, 1.12–9.90), and PICC maintenance interval (4–5 days vs ⩽3 days: OR, 0.06; 95% CI, 0.01–0.50; 5–7 days vs ⩽3 days: OR, 0.07; 95% CI, 0.02–0.31; 7–9 days vs ⩽3 days: OR, 0.10; 95% CI, 0.02–0.57). Conclusions: BMI, skin condition, skin indentation, allergic history, history of dermatitis, history of eczema, catheter insertion site, and PICC maintenance interval were independent risk factors for PICC-related skin injuries in cancer patients. This knowledge will guide future studies with formulating optimal treatment strategies for improving the skin health of cancer patients with PICC.