When wrongly used, guideline-based clinical decision support systems (CDSSs) may generate inappropriate propositions that do not match the recommendations provided by clinical practice guidelines (CPGs). The user may decide to comply with or react to the CDSS, and her decision may finally comply or not with CPGs. OncoDoc2 is a guideline-based CDSS for breast cancer management. We collected 394 decisions made by multidisciplinary meeting physicians in three hospitals where the CDSS was evaluated. We observed a global CPG compliance of 86.8% and a global CDSS compliance of 75.4%. Non-CPG compliance was observed in case of a negative reactance to the CDSS, when users did not follow a correct CDSS proposition (8.6% of decisions). Because of errors in patient data entry, OncoDoc2 delivered non-recommended propositions in 21.3% of decisions, leading to compliances with CDSS and CPGs of respectively 21.4% and 65.5%, whereas both compliances exceeded 90% when CDSS advices included CPG recommendations. Automation bias, when users followed an incorrect CDSS proposition explained the remaining non-compliance with CPGs (4.6% of decisions). Securing the use of CDSSs is of major importance to warranty patient safety and benefit of their potential to improve care.