OBJECTIVES The number of patients with schizofrenia in the Czech Republic amounts annually to approximately 126,000. Schizophrenia causes significant increases in mortality, shortening life expectancy by 25 years compared to the general population which implies high disease burden. The aim was to estimate the cost-effectiveness of long-acting paliperidone in the treatment with schizofrenia compared to oral risperidone, oral paliperidone and long-acting risperidone.  METHODS Cost-utility analysis was performed using a Markov model. The primary outcome was ICER/QALY. Oral risperidone, oral paliperidone and long-acting risperidone were selected as comparators. The basic components of the model include probabilities of relapse, individual hazard ratios for non-compliance by medication type and switch of treatment probabilities. Specific utilities for each health state were considered. Among relevant costs, reflecting payer's perspective, drug acquisition costs, monitoring costs, costs of relapses, follow-up care and adverse events were considered. RESULTS Long-acting paliperidone reached ICER of EUR 16,233/QALY compared to oral risperidone, EUR 15,058/QALY to oral paliperidone and EUR 335/QALY to long-acting risperidone. The robustness of the model was supported by one-way deterministic analysis and probabilistic sensitivity analysis, which gave stable results. Long-acting paliperidone was cost effective in 97% of the simulations compared to oral risperidone. Long-acting paliperidone treatment gained incremental 0.903 QALYs on average compared to oral risperidone. CONCLUSIONS The treatment of schizophrenia using long-acting paliperidone is associated with increased QALYs. It reduces incidence of adverse events, results in better prevention of relapses and can be considered a cost-effective treatment in the Czech Republic.