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Purpose In a critical care setting, we aimed to identify and solve physico-chemical drug incompatibilities in central-venous catheters considering the staffs’ knowledge and assumptions about incompatibilities. Methods (i) After positive ethical vote, an algorithm to identify incompatibilities was developed and applied. The algorithm was based on KIK® database and Stabilis® database, the drug label, and Trissel textbook. (ii) A questionnaire was created and used that asked staff for knowledge and assumptions about incompatibilities. (iii) A 4-step avoidance recommendation was developed and applied. Results (i) At least one incompatibility was identified in 64 (61.4%) of 104 enrolled patients. Eighty one (62.3%) of 130 incompatible combinations affected piperacillin/tazobactam and in 18 (13.8%) each furosemide and pantoprazole. (ii) 37.8% (n = 14) of the staff members participated in the questionnaire survey (median age: 31, IQR: 4.75 years). The combination of piperacillin/tazobactam and pantoprazole was incorrectly judged to be compatible by 85.7%. Only rarely felt the majority of respondents unsafe in administering drugs (median score: 1; 0, never to 5, always). (iii) In those 64 patients with at least one incompatibility, 68 avoidance recommendations were given, and all were fully accepted. In 44 (64.7%) of 68 recommendations “Step 1: Administer sequentially” was suggested as a avoidance strategy. In 9/68 (13.2%) “Step 2: Use another lumen”, in 7/68 (10.3%) “Step 3: Take a break”, and in 8/68 (11.8%) “Step 4: Use catheters with more lumens” were recommended. Conclusions Although incompatibilities were common, the staff rarely felt unsafe when administering drugs. Knowledge deficits correlated well with the incompatibilities identified. All recommendations were fully accepted.