Introduction: Diabetes mellitus type 1 and type 2 are linked to higher prevalence and occurrences of depression. Internet-based depression- and diabetes-specific cognitive behavioral therapies (CBT) can be effective in reducing depressive symptom severity and diabetes-related emotional distress. The aim of the study was to test whether disease-specific severity indicators moderate the treatment outcome in a 6-week minimally guided web-based self-help intervention on depression and diabetes (GET.ON Mood Enhancer Diabetes (GET.ON M.E.D.)) and to determine its effectiveness in a nonsuicidal severely depressed subgroup. Methods: Randomized controlled trial- (RCT-) based data (N = 253) comparing GET.ON M.E.D. to an online psychoeducation control group was used to test disease-specific severity indicators as predictors/moderators of a treatment outcome. Changes in depressive symptom severity and treatment response were examined in a nonsuicidal severely depressed subgroup (CES - D > 40; N = 40). Results: Major depressive disorder diagnosis at the baseline (pprf6 = 0.01), higher levels of depression (Beck Depression Inventory II; pprpo = 0.00; pprf6 = 0.00), and lower HbA1c (pprpo = 0.04) predicted changes in depressive symptoms. No severity indicator moderated the treatment outcome. Severely depressed participants in the intervention group showed a significantly greater reduction in depressive symptom severity (dprpo = 2.17, 95% Confidence Interval (CI): 1.39-2.96) than the control condition (dprpo = 0.92; 95% CI: 0.001-1.83), with a between-group effect size of dprpo = 1.05 (95% CI: 0.11-1.98). Treatment response was seen in significantly more participants in the intervention (4/20; 20%) compared to the control group (0/20, 0%; χ2 (2)(N = 40) = 4.44; p < 0.02). At the 6-month follow-up, effects were maintained for depressive symptom reduction (dpr6f = 0.71; 95% CI: 0.19-1.61) but not treatment response. Conclusion: Disease-specific severity indicators were not related to a differential effectiveness of guided self-help for depression and diabetes. Clinical meaningful effects were observed in nonsuicidal severely depressed individuals, who do not need to be excluded from web-based guided self-help. However, participants should be closely monitored and referred to other treatment modalities in case of nonresponse.