Background: Work-related stress is widespread among employees and associated with high costs for German society. Internet-based stress management interventions (iSMIs) are effective in reducing such stress. However, evidence for their cost-effectiveness is scant. Objective: The aim of this study was to assess the cost-effectiveness of a guided iSMI for employees. Methods: A sample of 264 employees with elevated symptoms of perceived stress (Perceived Stress Scale≥22) was assigned to either the iSMI or a waitlist control condition (WLC) with unrestricted access to treatment as usual. Participants were recruited in Germany in 2013 and followed through 2014, and data were analyzed in 2017. The iSMI consisted of 7 sessions plus 1 booster session. It was based on problem-solving therapy and emotion regulation techniques. Costs were measured from the societal perspective, including all direct and indirect medical costs. We performed a cost-effectiveness analysis and a cost-utility analysis relating costs to a symptom-free person and quality-adjusted life years (QALYs) gained, respectively. Sampling uncertainty was handled using nonparametric bootstrapping (N=5000). Results: When the society is not willing to pay anything to get an additional symptom-free person (eg, willingness-to-pay [WTP]=0), there was a 70% probability that the intervention is more cost-effective than WLC. This probability rose to 85% and 93% when the society is willing to pay 1000 and 2000, respectively, for achieving an additional symptom-free person. The cost-utility analysis yielded a 76% probability that the intervention is more cost-effective than WLC at a conservative WTP threshold of 20,000 (US $25,800) per QALY gained. Conclusions: Offering an iSMI to stressed employees has an acceptable likelihood of being cost-effective compared with WLC.