Non-adherence to antipsychotic medication is commonly found in schizophrenia and other psychotic disorders, thus forming a major obstacle to long-term maintenance treatment and contributing to high relapse rates. With limited evidence on the success of interventions in enhancing medication adherence, this controlled trial was designed to test and evaluate the effectiveness of an adherence therapy (AT) for outpatients with schizophrenia spectrum disorders, based on a motivational interviewing approach over a six-month follow-up period.A single-blind, randomized controlled trial with a repeated-measures, two parallel groups design was conducted in a random sample of 114 participants with schizophrenia spectrum disorders in one community psychiatric nursing service. After pre-test, the participants were randomly assigned to either an eight-session course of AT plus usual care or usual psychiatric care (n = 57 per group). The main outcomes, including medication adherence, symptom severity, insight into treatment, hospitalization rate, and functioning, were measured at baseline and immediately and six months post-intervention.A total of 110 participants completed this trial and thus the attrition rate was 3.5%. Results of repeated-measures analysis of variance followed by Helmert's contrasts test indicated that the AT participants reported significantly greater improvements in their insight into illness and/or treatment, psychosocial functioning, symptom severity, number of re-hospitalizations, and medication adherence (F = 5.01 to 7.45, P = 0.007 to 0.030) over six months follow-up, when compared with usual care.Motivational interviewing-based AT for people with schizophrenia can be effective to reduce symptom severity and re-hospitalizations, and improve medication adherence, functioning, and insight into illness and/or treatment over a medium term (six months) period of follow-up. Further study on the effects of AT in people with psychotic disorders in terms of diverse sociodemographic and illness characteristics, and a longer term (for example, over 12 months) follow-up period is recommended.The trial was registered at Clinicaltrials.gov (identifier: NCT01780116) on 6 July 2014.