There is good evidence that clozapine is more efficacious than first-generation antipsychotic drugs in resistant schizophrenia. It is less clear if clozapine is more effective than the other second-generation antipsychotic (SGA) drugs. A noncommercially funded, pragmatic, open, multisite, randomized controlled trial was conducted in the United Kingdom National Health Service (NHS). Participants were 136 people aged 18-65 with DSM-IV schizophrenia and related disorders whose medication was being changed because of poor clinical response to 2 or more previous antipsychotic drugs. Participants were randomly allocated to clozapine or to one of the class of other SGA drugs (risperidone, olanzapine, quetiapine, amisulpride) as selected by the managing clinician. Outcomes were assessed blind to treatment allocation. One-year assessments were carried out in 87% of the sample. The intent to treat comparison showed no statistically significant advantage for commencing clozapine in Quality of Life score (3.63 points; CI: 0.46-7.71; p = .08) but did show an advantage in Positive and Negative Syndrome Scale (PANSS) total score that was statistically significant (-4.93 points; CI: -8.82 to -1.05; p = .013) during follow-up. Clozapine showed a trend toward having fewer total extrapyramidal side effects. At 12 weeks participants who were receiving clozapine reported that their mental health was significantly better compared with those receiving other SGA drugs. In conclusion, in people with schizophrenia with poor treatment response to 2 or more antipsychotic drugs, there is an advantage to commencing clozapine rather than other SGA drugs in terms of symptom improvement over 1 year.