The large numbers of partial clozapine responders represent a major therapeutic challenge. Unfortunately, there are no clear data to support how best to treat these patients. This study examines the efficacy and safety of adjunctive risperidone in a well-defined treatment-resistant population optimally treated with clozapine. A total of 69 inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder entered a 16-week double-blind, placebo-controlled, randomized clinical trial. Of them, 33 participants were randomized to risperidone and 36 were randomized to placebo. There was no significant group difference in the predefined response criteria. There were modest group differences for Brief Psychiatric Rating Scale (BPRS) positive symptoms, which were significant in the completer analysis (F=5.70; df=1, 70.3; p=0.02; ES=0.27) but not the intent-to-treat (ITT) analyses (F=3.01; df=1, 77.5; p=0.09; ES=0.19). A similar pattern was found for the BPRS total score, with the completer analysis showing a significant improvement in the risperidone group (F=5.21; df=1, 64.9; p=0.03; ES=0.27), whereas the ITT analysis was not significant (F=3.52; df=1, 71.3; p=0.06; ES=0.22). In addition, there was a small, but significant, group difference for negative symptoms, as measured by the SANS total score, which favored the risperidone group (F=5.67; df=1, 78.7; p=0.02; ES=0.24). There were no significant group differences on safety measures, including neuropsychological test and extrapyramidal symptom scores. A significant elevation of prolactin in the risperidone group was observed. The study results suggest that adjunctive risperidone may have a modest benefit for treatment-resistant clozapine patients. The study results are discussed in the context of previous double-blind studies of adjunctive risperidone. (clinicaltrials.gov, trial number: NCT00056498).