Background and objective: Frequent attender is the largest group to whom health care resources are allocated. Therefore potential interventions should be targeted at this group. Nurse-based case management considers frequent attenders' (FAs') needs for care as a whole and thus may reduce the use of other health services operators' resources. The objective of this study is to evaluate the effects of nurse-led case management on adherence to health regimens, depression, somatization and hypochondriasis in FAs. Methods: The study is a quasi-experimental intervention trial, carried out as a prospective 2-year follow-up design with an intervention group (n = 285) and a control group (n = 435). The hypothesis was that nurse-led case management based intervention would have a positive impact on FAs' adherence to health regimens, somatization, hypochondriasis, and depression. The intervention patients received nurse-led case management which included an evaluation of patient needs and resources, an individualized care plan, the coordination of multidisciplinary services, and support for self-management. The control patients received the usual care, which means patient support and education during visits to the health center. The data were collected from at least 18 years of age frequent attenders by self-reported instruments: the Adherence of Chronic Disease Inventory, the Whiteley Index, the Symptom Checklist-90-R and Beck Depression Inventory, and one-and two-year follow-ups between October 2008 and May 2011. Results: The intervention had an uplifting effect on the FAs' mood, and there was a statistically significant difference between the intervention patients and the control patients (p = .03). Intervention reduced somatization with FAs, and it improved FAs' adherence to health regimens, but there was not a statistically significant difference between groups. Hypochondriasis increased in the intervention group compared to the control group after intervention (p = .01). Conclusions: Nurse-led case management has a positive effect on FAs' depression symptoms, somatization, and adherence to health regimens. The results will be useful in developing effective nurse-led interventions and support methods for FAs with complex long-term health conditions. Hypochondriasis increased in the intervention group although the purpose was for the community matron to discuss with FAs and reduce their concerns.