We assessed the safety of a new clinical decision support system (CDSS) for nurses on Australia’s national consumer helpline. Accuracy and safety of triage advice was assessed by testing the CDSS using 78 standardised patient vignettes (48 published and 30 proprietary). Testing was undertaken in two cycles using the CDSS vendor’s online evaluation tool (Cycle 1: 47 vignettes; Cycle 2: 41 vignettes). Safety equivalence was examined by testing the existing CDSS with the 47 vignettes from Cycle 1. The new CDSS triaged 66% of vignettes correctly compared to 57% by the existing CDSS. 15% of vignettes were overtriaged by the new CDSS compared to 28% by the existing CDSS. 19% of vignettes were undertriaged by the new CDSS compared to 15% by the existing CDSS. Overall performance of the new CDSS appears consistent and comparable with current studies. The new CDSS is at least as safe as the old CDSS.