BACKGROUND: Crisis Resolution Home Treatment (CRHT) is an alternative to inpatient treatment for acute psychiatric crises management. However, evidence on CRHT effectiveness is still limited. In the Canton of Ticino (Southern Switzerland), in 2016 the regional public psychiatric hospital replaced one acute ward with a CRHT. The current study was designed within this evaluation setting to assess the effectiveness of CRHT compared to standard inpatient treatment. METHODS: CRHT was offered to patients aged 18 to 65 with an acute psychiatric crisis that would have required hospitalization. We used a natural experiment based on geography, where intervention and control groups were formed according to the place of residence. Primary endpoints were reduction of psychiatric symptoms at discharge measured using the Health of the Nation Outcome Scales, treatment duration in days, and rate and length of readmissions during a two-year follow-up period after discharge. Safety during the treatment period was measured with the number of serious adverse events (suicide/suicide attempts, major self-harm episodes, acute alcohol/drug intoxications, aggressions to caregivers or family members). We used linear, log-linear and logistic regression models with propensity scores for the main analysis. RESULTS: We enrolled 321 patients; 67 were excluded because the treatment period was too short and 17 because they were transferred before the end of the treatment. Two hundred thirty-seven patients were available for data analysis, 93 in the intervention group and 144 in the control group. No serious adverse event was observed during the treatment period in both groups. Reduction of psychiatric symptoms at discharge (p-value = 0.359), readmission rates (p-value = 0.563) and length of readmissions (p-value = 0.770) during the two-year follow-up period did not differ significantly between the two groups. Treatment duration was significantly higher in the treatment group (+ 29.6% on average, p-value = 0.002). CONCLUSIONS: CRHT was comparable to standard hospitalization in terms of psychiatric symptoms reduction, readmission rates and length of readmissions, but it was also characterized by a longer first treatment period. However, observational evidence following the study indicated that CRHT duration constantly lowered over time since its introduction in 2016 and became comparable to hospitalization, showing therefore to be an effective alternative also in terms of treatment length. TRIAL REGISTRATION: ISRCTN38472626 (17/11/2020, retrospectively registered).