Abstract Background Among glioma patients, depression is estimated to be more prevalent than in both the general population and the cancer patient population. This can have negative consequences for both patients and their primary informal caregivers (e.g., a spouse, family member or close friend). At present, there is no evidence from randomized controlled trials for the effectiveness of psychological treatment for depression in glioma patients. Furthermore, the possibility of delivering mental health care through the internet has not yet been explored in this population. Therefore, a randomized controlled trial is warranted to evaluate the effects of an internet-based, guided self-help intervention for depressive symptoms in glioma patients. Methods/design The intervention is based on problem-solving therapy. An existing 5-week course is adapted for use by adult glioma patients with mild to moderate depressive symptoms (Center for Epidemiology Studies Depression Scale score ≥12). Sample size calculations yield 126 glioma patients to be included, who are randomly assigned to either the intervention group or a waiting list control group. In addition, we aim to include 63 patients with haematological cancer in a non-central nervous system malignancy control group. Assessments take place at baseline, after 6 and 12 weeks, and after 6 and 12 months. Primary outcome measure is the change in depressive symptoms. Secondary outcome measures include health-related quality of life, fatigue, costs and patient satisfaction. In addition, all patients are asked to assign a primary informal caregiver, who does not participate in the intervention but who is asked to complete similar assessments. Their mood, health-related quality of life and fatigue is evaluated as well. Discussion This is the first study to evaluate the effects of problem-solving therapy delivered through the internet as treatment for depressive symptoms in glioma patients. If proven effective, this treatment will contribute to the mental health care of glioma patients in clinical practice. Trial registration Netherlands Trial Register NTR3223