Background: Hand hygiene is one of the most effective measures to prevent healthcare-associated infections and transmission of multidrug-resistant organisms in healthcare settings. The WHO proposes a multimodal intervention strategy to improve hand hygiene in healthcare settings. In 2008, a voluntary national campaign for hand hygiene was implemented in the German healthcare system. The objective of this study was to evaluate participation, practices, and performance of hand hygiene in German acute-care hospitals. Methods: In 2008 a national hand hygiene campaign began in Germany. Based on voluntary participation, the campaign’s goal was to implement the WHO 5 Moments model, to establish a national surveillance system for compliance to hand hygiene, to improve availability of alcohol-based hand-rub (ABHR) dispensers at points of care, and to implement interdisciplinary executive boards at each hospital to ensure sustainable implementation. Annual data on ABHR consumption and patient days (PD) were collected within the national surveillance system (HAND-KISS) on the individual ward level and were validated. Direct observation of compliance was performed according the recommendations of the WHO. Results: Overall, 1,047 of 1,942 acute-care hospitals in Germany participated in the national hand hygiene campaign in 2018, covering 81,571,917 patient days. Moreover, 9,360 regular wards (RWs), 338 intermediate care units (IMCs) and 1,342 intensive care units (ICUs) provided data on ABHR consumption. Between 2007 and 2018 in the ICU, ABHR consumption increased continuously from 70 mL/PD (IQR, 52–98) to 129 mL/PD (IQR, 102–162). In intermediate care units, ABHR consumption increased from 40 mL/PD (IQR, 15–54) to 67 mL/PD (IQR, 46–95), and on regular wards, ABHR consumption increased from 14 mL/PD (IQR, 10–21) to 29 mL/PD (IQR, 22–39). These increases were especially pronounced in wards that continuously provided annual data for ABHR consumption over the past 12 years. In 2014, electronic documentation for direct observation of compliance to hand hygiene was established. From 2014 until 2018, 1,598,209 opportunities were observed on 1,907 wards of 422 hospitals. The median directly observed compliance in 2018 was 76% (IQR, 66%–84%). Median compliance to the 5 Moments was 71% (IQR, 57%–82%) before touching a patient, 68% (IQR, 51%–85%) before clean or aseptic procedures, 83% (IQR, 72%–92%) after body fluid exposure or risk, 84% (IQR, 75%–90%) after touching a patient, and 74% (IQR, 61%–84%) after touching patient surroundings. Conclusions: The WHO multimodal intervention strategy has been successfully established in German acute-care hospitals. A surveillance system for ABHR consumption and direct observation of compliance to hand hygiene are widely used by hospitals in Germany. Hand hygiene practices have significantly improved in the German healthcare system.