Although grief-focused cognitive behavior therapies are the most empirically supported treatment for prolonged grief disorder, many people find this treatment difficult. A viable alternative for treatment is mindfulness-based cognitive therapy. To examine the relative efficacies of grief-focused cognitive behavior therapy and mindfulness-based cognitive therapy to reduce prolonged grief disorder severity. A single-blind, parallel, randomized clinical trial was conducted among adults aged 18 to 70 years with prolonged grief disorder, as defined in the International Classification of Diseases, 11th Revision, and assessed by clinical interview based on the Prolonged Grief-13 (PG-13) scale. Those with severe suicidal risk, presence of psychosis, or substance dependence were excluded. Between November 2012 and November 2022, eligible participants were randomized 1:1 to eleven 90-minute sessions of grief-focused cognitive behavior therapy or mindfulness-based cognitive therapy at a traumatic stress clinic in Sydney, Australia, with follow-up through 6 months. Both groups received once-weekly 90-minute individual sessions for 11 weeks. Grief-focused cognitive behavior therapy comprised 5 sessions of recalling memories of the deceased, plus cognitive restructuring and planning future social and positive activities. Mindfulness-based cognitive therapy comprised mindfulness exercises adapted to tolerate grief-related distress. The primary outcome was change in prolonged grief disorder severity measured by the PG-13 scale assessed at baseline, 1 week posttreatment, and 6 months after treatment (primary outcome time point), as well as secondary outcome measures of depression, anxiety, grief-related cognition, and quality of life. The trial included 100 participants (mean [SD] age, 47.3 [13.4] years; 87 [87.0%] female), 50 in the grief-focused cognitive behavior therapy condition and 50 in the mindfulness-based cognitive therapy condition. Linear mixed models indicated that at the 6-month assessment, participants in the grief-focused cognitive behavior therapy group showed greater reduction in PG-13 scale score relative to those in the mindfulness-based cognitive therapy group (mean difference, 7.1; 95% CI, 1.6-12.5; P = .01), with a large between-group effect size (0.8; 95% CI, 0.2-1.3). Participants in the grief-focused cognitive behavior therapy group also demonstrated greater reductions in depression as measured on the Beck Depression Inventory than those in the mindfulness-based cognitive therapy group (mean difference, 6.6; 95% CI, 0.5-12.9; P = .04) and grief-related cognition (mean difference, 14.4; 95% CI, 2.8-25.9; P = .02). There were no other significant differences between treatment groups and no reported adverse events. In this study, grief-focused cognitive behavior therapy conferred more benefit for core prolonged grief disorder symptoms and associated problems 6 months after treatment than mindfulness-based cognitive therapy. Although both treatments may be considered for prolonged grief disorder, grief-focused cognitive behavior therapy might be the more effective choice, taking all factors into consideration. anzctr.org.au Identifier: ACTRN12612000307808.