OBJECTIVES: This evaluation aimed to assess the cost-effectiveness of paliperidone palmitate in different lines of therapy for schizophrenia patients compared to the current patient pathway. METHODS: A Markov model was developed that examined the use of five different treatment sequences, each involving paliperidone palmitate at different points in the sequence. Variations in treatment sequences were assessed to examine their impact on the model’s findings, and were compared with a comparator treatment sequence reflecting current practice. The model simulated the three main schizophrenic health states of remission, minor relapse and major relapse. Adherence with medication is also taken into consideration due to its impact on resource use, quality of life and the probability of relapse. The model adopted a timeline of five years and used a Spanish health care provider perspective. Drug costs are assumed to be ex factory. RESULTS: The difference in costs associated with introduction of paliperidone palmitate at different moments of patient course ranges from an additional €260 when used as a fourth-line therapy to a reduction of €2,217 (i.e. cost saving) when directly used as a second-line therapy after a course of daily risperidone treatment. Cost savings arose due to reduced rates of relapse.  All five treatment sequences resulted in an increase in QALYs, ranging from 0.043 QALYs for fourth-line therapy to 0.124 QALYs per patient for second-line treatment. Second-line treatment was dominant to all other treatment sequences. Probabilistic sensitivity analysis suggests that the probability of paliperidone palmitate being cost-effective as a second-line therapy is 96.8% at both €30,000 and €45,000 thresholds. One year analysis gave similar results, with palmitate paliperidone as second-line therapy also dominant to all other treatment sequences. CONCLUSIONS: Paliperidone palmitate used as second line after a course of daily risperidone treatment is the dominant alternative when compared to the other scenarios.