Background: Attempted suicide is the main risk factor for repeated suicidal behavior. However, the evidence for follow-up treatments of these patients is limited. The objective of the present study was to evaluate the efficacy of ASSIP (Attempted Suicide Short Intervention Program) in reducing suicidal behavior. ASSIP is a novel brief therapy based on a patient-centered model of suicidal behavior, with an emphasis on early therapeutic alliance. Methods and Findings: Patients who had recently attempted suicide were randomly allocated to treatment as usual (N=60) or treatment as usual plus ASSIP (N=60). ASSIP participants received three therapy sessions followed by regular contact through personalized letters over 24 months. Participants considered to be at high risk of suicide were included, 63% were diagnosed with an affective disorder, and 50% had a history of prior suicide attempts. Clinical exclusion criteria were habitual self-harm, serious cognitive impairment, and psychotic disorder. Study participants completed a set of psychosocial and clinical questionnaires every 6 months over a 24-months follow-up period. The study represents a real-world clinical setting at an outpatient clinic of an university hospital of psychiatry. Primary outcome measure was repeat suicide attempts during the 24-months follow-up period. Secondary outcome measures were suicidal ideation and healthcare utilization. Furthermore, effects of prior suicide attempts, depression at baseline, diagnosis, and therapeutic alliance on outcome were investigated. During the 24-months follow-up period, 5 repeat attempts were recorded in the ASSIP group and 41 attempts in the control group. The rates of participants reattempting suicide at least once were 8.3% (n=5) and 26.7% (n=16). ASSIP was associated with an approximately 80% reduced risk of repeat episodes (Wald ?21=13.1; 95% CI 12.4-13.7; p=.0004). ASSIP participants spent 72% fewer days in hospital during follow-up (ASSIP: 29 days; control group: 105 days; W=94.5, p=.038). Higher scores of patient-rated therapeutic alliance in this group were associated with a lower rate of repeat suicide attempts. Prior suicide attempts, depression, and a diagnosis of personality disorder at baseline did not significantly affect outcome. Participants with a diagnosis of borderline personality disorder (n=20) had more previous suicide attempts and a higher number of reattempts. Key study limitations were missing data and dropout rates. Although both were generally low they increased during follow-up. At 24 months the group difference between the dropout rates was significant: ASSIP: 7% (n=4), control: 22% (n=13). A further limitation is that we do not have detailed information of the co-active follow-up treatment apart from the 6-monthly self-reports on the setting and the duration of treatment as usual. Conclusions: ASSIP, a manual-based brief therapy for patients who had recently attempted suicide, administered in addition to the usual clinical treatment, was efficacious in reducing suicidal behavior in a real-world clinical setting. ASSIP fulfills the need for an easy to administer low-cost intervention. Large pragmatic trials will be needed to conclusively establish the efficacy of ASSIP and replicate our findings in other clinical settings. ClinicalTrials.gov Identifier: NCT02505373