Antiseptic bathing has garnered attention in an effort to reduce hospital-acquired infections. Previous studies have shown the efficacy of antiseptic bathing in high-risk environments, such as intensive care units (ICUs), using chlorhexidine. In this study we aimed to evaluate the effectiveness of octenidine as a potential alternative due to its established popularity and widespread use in Europe.We compared the rates of ICU-acquired primary bacteremia and ICU-acquired multidrug-resistant organisms (MDROs) in a multicenter, cluster-randomized, double-blind, placebo-controlled, cross-over study using octenidine-impregnated and placebo washcloths. On 44 ICUs in 23 hospitals throughout Germany, we compared individual ICUs with themselves over two 12-month time periods. All data were obtained digitally via hospital information systems as individual ward-movement data and microbiological test results; both endpoints were algorithmically derived.104,039 ICU episodes from 93,438 patients with 712,784 microbiological test results were analyzed, thereby detecting 1508 cases of ICU-acquired primary bacteremia and 1871 cases of ICU-acquired MDRO. Bathing with octenidine-impregnated washcloths prevented ICU-acquired primary bacteremia; a risk reduction of 17% was seen homogeneously across all participating ICUs (adjusted hazard ratio (HR) 0.83, 95% confidence interval (CI) [0.75; 0.92], p = 0.0003). This reduction affected predominantly coagulase-negative staphylococci (53%) and enterococci (17%). However, no intervention effect was seen for ICU-acquired MDROs (adjusted HR 0.98, 95% CI [0.83; 1.15]). Heterogeneity among intra-ICU intervention effects on MDRO acquisition was substantial.Antiseptic bathing with octenidine may be effective in preventing ICU-acquired primary bacteremia, particularly due to Gram-positive bacteria and common skin commensals.