Patients in intensive care units (ICUs) are at high risk of drug–drug interactions (DDIs) due to polypharmacy. Little is known about type and frequency of DDIs within German ICUs. Clinical pharmacists’ interventions (PI) recorded in a national database (ADKA-DokuPIK) were filtered for ICU patients. Binary DDIs involving ≥1 anti-infective agent with >1 database entry were selected. A modified two-step Delphi process with a group of senior hospital pharmacists was employed to evaluate selected DDIs for clinical relevance by using a five-point scale and to develop guidance for clinical practice. In total, 16,173 PI were recorded, including 1836 (11%) DDIs in the ICU setting. Of the latter, 41% (756/1836) included ≥1 anti-infective agent, 32% (590/1836) were binary DDIs, and 25% (455/1836) were listed at least twice. This translates into 88 different DDIs, 74% (65/88) of which were rated as being clinically relevant by our expert panel. The majority of DDIs (76% [67/88]) included macrolides, antifungals, or fluoroquinolones. This percentage was even higher in DDIs being rated as clinically relevant by the experts (85% [55/65]). It is noted that an inter-professional discussion and approach is needed in the individual patient management of DDIs. The guidance developed might be a tool for decision support.