Pin-site infections remain a common clinical complication in patients with external fixators. Pin-site care is commonly performed with either chlorhexidine-alcohol solution or povidone-iodine solution. This study aimed to investigate the superiority of chlorhexidine-alcohol solution versus povidone-iodine solution for external fixator pin-site care in pin-site infection. This prospective randomized clinical trial using an open, parallel-group design was conducted in a single Spanish hospital. Eligible consenting patients from November 2018 to May 2019 who underwent placement of an external fixator were included. Patients were randomly assigned to receive pin-site care using either a 2% chlorhexidine-alcohol solution or a 10% povidone-iodine solution. The primary endpoint was the development of a pin-site infection. In total, 568 pins were analyzed (128 patients, with a mean of 4.3 pins per patient). No significant differences were found between groups. However, statistically significant differences were found regarding time and infection variables. The longer the person had the fixator, the higher the risk of infection, t(x) = 5.49, p = .002. Both chlorhexidine-alcohol and povidone-iodine solutions are equally effective antiseptic agents for the prevention of infections in external fixators.