Aim: The aim of this research is to examine the 6-month effects of an Internet-based guided self-help intervention for comorbid depressive symptoms in people with diabetes. Methods: Participants (n = 260) with Type 1 or 2 diabetes and elevated depressive symptoms [Center for Epidemiological Studies Depression Scale (CES-D) ≥ 23] were randomly assigned to a guided Internet-based self-help intervention or a control condition (treatment as usual + online psychoeducation about depression). The primary outcome was a change in depressive symptom severity (CES-D) from baseline to 6-month follow-up. The secondary outcomes included numbers of people achieving treatment response (reliable change of depressive symptoms) and remission (CES-D ≤ 16), as well as the effects on glycaemic control, diabetes-related emotional distress and diabetes acceptance. Repeated measures analysis of variance examined between-group differences using intent-to-treat principles. Results: Both conditions showed improvements in depression severity: intervention condition, d = 1.48 [95% confidence interval (95% CI): 1.21 to 1.76]; control condition d = 0.55 (95% CI: 0.30 to 0.80). Changes were significantly greater in the intervention condition with a large between-group effect size (d = 0.83, 95% CI: 0.57 to 1.08). Accordingly, effects on response [relative risk (RR) = 2.60 (95% CI: 2.01 to 3.36), P < 0.001] and remission [RR = 3.36 (95% CI: 2.98 to 5.44), P < 0.001] were in favour of the intervention group, as were differences in change in diabetes emotional distress (d = 0.50, 95% CI: 0.04 to 0.54), and physical and mental functioning [Short Form Health Survey (SF-12) Physical d = 0.27 (95% CI: 0.01 to 0.51) and SF-12 Mental d = 0.68 (95% CI: 0.11 to 0.40)]. The intervention group was not superior with regard to glycaemic control, diabetes self-management and diabetes acceptance. Conclusions: The trial indicates that Internet-based guided self-help treatments for depression in people with diabetes can have sustained effects on depressive symptoms, well-being and emotional distress associated with diabetes.