Major depressive disorder (MDD) is a highly prevalent and disabling disorder. This study examines two psychotherapy methods for MDD, behavioral activation (BA), and metacognitive therapy (MCT), when applied as outpatient treatments to severely affected patients. The study was conducted in a tertiary outpatient treatment center. Patients with a primary diagnosis of MDD (N = 122) were included in the intention-to-treat sample (55.7% female, mean age 41.9 years). Participants received one individual and one group session weekly for 6 months (M). Assessments took place at baseline, pretreatment, mid-treatment (3 M), post-treatment (6 M), and follow-up (12 M). The primary outcome was depressive symptomatology assessed by the Hamilton Rating Scale for Depression at 12 M follow-up. Secondary outcomes included general symptom severity, psychosocial functioning, and quality of life. Linear mixed models indicated a change in depressive symptoms (F(2, 83.495) = 12.253, p < 0.001) but no between-group effect (F(1, 97.352) = 0.183, p = 0.670). Within-group effect sizes were medium for MCT (post-treatment: d = 0.610; follow-up: d = 0.692) and small to medium for BA (post-treatment: d = 0.636, follow-up: d = 0.326). In secondary outcomes, there were improvements (p ≤ 0.040) with medium to large within-group effect sizes (d ≥ 0.501) but no between-group effects (p ≥ 0.304). Response and remission rates did not differ between conditions at follow-up (response MCT: 12.9%, BA: 13.3%, remission MCT: 9.7%, BA: 10.0%). The deterioration rate was lower in MCT than in BA (χ21 = 5.466, p = 0.019, NTT = 7.4). Both MCT and BA showed symptom reductions. Remission and response rates were lower than in previous studies, highlighting the need for further improvements in adapting/implementing treatments for severely affected patients with MDD.