OBJECTIVES: Paliperidone palmitate has demonstrated non-inferior efficacy to risperidone long acting injectable (LAI) for the treatment of schizophrenia in previous studies. The objective of this analysis was to assess the cost effectiveness of paliperidone palmitate relative to risperidone LAI, based on the cost-utility analysis described in the current NICE Guidelines for the Management of Schizophrenia.  The analysis was undertaken from the perspective of NHS Wales and was submitted to the All Wales Medicines Strategy Group for evaluation.  METHODS: A decision-analytic Markov model was developed to estimate the cost-utility of paliperidone palmitate relative to risperidone LAI. The model adopted an annual cycle length. Patients who entered the model initiated either paliperidone palmitate or risperidone LAI and could subsequently transition between five health states during each annual cycle. AEs associated with each intervention were derived from literature. Utility values were derived from a community-based study, using trade-off technique to elicit HRQoL for schizophrenia according to frequency of injections. Resource use data was sourced from the NICE core model/guidelines, Welsh clinical experts, and a UK Delphi panel. Unit costs were derived from the British National Formulary, NHS reference costs, and the Personal Social Services Research Unit reports. Costs and outcomes were evaluated over a 10-year horizon, and discounted at 3.5%. Results were presented as incremental costs/QALY. Uncertainty was addressed via deterministic and probabilistic sensitivity analyses. RESULTS: The base case analyses demonstrated that paliperidone palmitate would incur lower costs (-£3,773) and generate more quality adjusted life years (QALYs) (+0.13) than risperidone LAI. This indicated that paliperidone palmitate ‘dominated’ risperidone LAI. Extensive scenario/sensitivity analyses confirmed the robustness of the results CONCLUSIONS: Compared with risperidone LAI, paliperidone palmitate is a cost-effective therapy for the treatment of schizophrenia in adult patients in NHS Wales.