<b><i>Introduction:</i></b> Chronic loneliness has been linked to many adverse outcomes, including mental health problems. Psychological treatment of loneliness can be effective, but the evidence base is limited. <b><i>Objective:</i></b> To investigate the efficacy of 2 internet-based interventions based on cognitive behavioral therapy (ICBT) and interpersonal psychotherapy (IIPT) relative to a wait-list control group and each other. <b><i>Methods:</i></b> A total of 170 participants were recruited and randomized to either 9 weeks of ICBT (<i>n</i> = 68), IIPT (<i>n</i> = 68), or a wait-list condition (<i>n</i> = 34). The primary outcome was loneliness, measured using the UCLA Loneliness Scale before, during, and after treatment. Secondary measures of psychiatric disorders and quality of life were administered before and after treatment. Follow-up was conducted 4 months after the treatment had ended. Primary outcome data were analyzed using growth curve modeling. Secondary outcomes were analyzed using robust regression models. The trial was preregistered (ClinicalTrials.gov ID: NCT03807154). <b><i>Results:</i></b> The ICBT condition had a significantly greater impact on loneliness compared to the wait-list and IIPT conditions. Effect sizes were moderate to large (Cohen <i>d</i> = 0.71) compared to the wait-list and moderate (<i>d</i> = 0.53) compared to IIPT. The IIPT condition did not differ significantly from the wait-list. Both active treatments led to significant increases in quality of life. Only the ICBT group had significantly lower symptoms of depression and generalized anxiety compared to the wait-list group. Treatment gains were maintained but not improved at follow-up. <b><i>Conclusions:</i></b> ICBT can be an efficacious option for alleviating loneliness. The IIPT intervention was not as effective.