Background: Recent evidence suggests the effectiveness of stepwise, targeted approaches for the prevention of lifestyle-related diseases with combinations of web-based and face-to-face interventions showing promising results. Objective: This paper reports on 1-year changes in health-risk behaviors, BMI, self-rated health, mental well-being, and risk of disease at 1-year follow-up after participation in a stepwise intervention that targeted persons at high risk of disease and persons with health-risk behavior. To this end, we distinguish between participants who took up the full intervention (web-based plus face-to-face) and those who received only the web-based intervention. Methods: The Early Detection and Prevention (Danish acronym: TOF) pilot study was conducted as a nonrandomized, 1-year follow-up intervention study in two municipalities in the Region of Southern Denmark. A total of 9400 citizens born between 1957 and 1986 (aged 29 to 60 years) were randomly sampled from participating general practitioner (GP) patient-list systems and were invited to take part in the study. Participants were subsequently stratified into risk groups based on their responses to a questionnaire on health-risk behavior and data from their GP’s electronic patient record (EPR) system. All participants received a digital personal health profile with individualized information on current health-risk behavior and targeted advice on relevant health-risk behavior changes. In addition, patients at high risk of disease, as indicated by their digital health profile, were offered a targeted intervention at their GP. Patients who were not deemed at high risk of disease but who exhibited health-risk behaviors were offered a targeted intervention at their municipal health center (MHC). At 1-year follow-up, health-risk behaviors, self-rated health, BMI, and mental well-being were reassessed by questionnaire, and current information on diagnoses and medical treatment was retrieved from the EPRs. Results: Of 598 patients at high risk of disease or with health-risk behavior, 135 took up the targeted intervention at their GP or MHC and 463 received the personal health profile only. From baseline to 1-year follow-up, the number of patients with unhealthy eating habits decreased, mean mental well-being increased, and smoking prevalence decreased in patients who had received the digital personal health profile alone. Among patients who took up the targeted intervention, unhealthy eating habits and sedentary lifestyles decreased and significant reductions in mean BMI were observed. At 1-year follow up, no health-risk behaviors were detected among 17.4% of patients who at baseline had exhibited health-risk behaviors or high risk of disease. Conclusions: A stepwise targeted preventive approach using web-based and face-to-face elements may lead to favorable lifestyle changes. Specifically, a web-based approach may improve smoking and eating habits and mental well-being, whereas supplementary face-to-face interventions may be necessary to improve exercise habits and BMI.