To conduct an economic evaluation of a tailored e-learning program, which successfully improved practice nurses' smoking cessation guideline adherence. Methods: The economic evaluation was embedded in a randomized controlled trial, in which 269 practice nurses recruited 388 smoking patients. Cost-effectiveness was assessed using guideline adherence as effect measure on practice nurse level, and continued smoking abstinence on patient level. Cost-utility was assessed on patient level, using patients' Quality Adjusted Life Years (QALYs) as effect measure. Results: The e-learning program was likely to be cost-effective on practice nurse level, as adherence to an additional guideline step cost s1,586. On patient level, cost-effectiveness was slightly likely after six months (cost per additional quitter: s7,126), but not after twelve months. The cost-utility analysis revealed slight cost-effectiveness (cost per QALY gained: s18,431) on patient level. Conclusion: Providing practice nurses with a tailored e-learning program is cost-effective to improve their smoking cessation counseling. Though, cost-effectiveness on patient level was not found after twelve months, potentially resulting from smoking relapse. Practice implications: Widespread implementation of the e-learning program can improve the quality of smoking cessation care in general practice. Strategies to prevent patients' smoking relapse should be further explored to improve patients' long-term abstinence.