Clinical decision support systems (CDSSs) have the potential to increase guideline adherence, but factors of success are not yet understood. ASTI guiding mode (ASTI-GM) is an on-demand guideline-based CDSS where the user navigates in a knowledge base to get the best treatment for a given patient. We conducted a web-based evaluation of ASTI-GM, carried out as a before-after study, where general practitioners (GPs) were asked to solve 5 clinical cases, first without ASTI-GM, then using the system. Of the 136 GPs that resolved the case on the management of hypertension, compliance with best practices increased from 69.1% to 80.9% with ASTI-GM. When the navigation matched the set of patient parameters described in the clinical case, the increase was even higher and reached 92.9%. E-iatrogenesis has been measured at 19.1%, with 5.1% of commission errors, 8.1% of negative reactance, and 5.9% of neutral reactance. Role of physicians' reactance in noncompliance with guideline-based CDSSs should be further investigated.