OBJECTIVES: Patients with chronic schizophrenia are difficult to manage and costly to the health system. The European Medicines Agency has approved paliperidone palmitate (PP-LAI; Xeplion®), an atypical antipsychotic depot which is administered monthly. However, its pharmacoeconomic profile in Portugal is unknown. Therefore, we conducted a cost-effectiveness analysis from the analytic viewpoint of the Portuguese National Health Service. METHODS: PP-LAI was compared with long acting injectable forms of risperidone (RIS-LAI) and haloperidol (HAL-LAI) as well as oral drugs (oral-OLZ) using a 1-year decision tree previously used in Europe and adapted to Portugal with guidance from clinical experts. We obtained clinical information and costs from literature sources and published lists. Clinical outcomes included relapses (both requiring and not requiring hospitalization), days with relapse, and quality-adjusted life-years (QALYs).  Costs were expressed in 2015 euros. Economic outcomes included a cost-utility (incremental cost/QALY) and cost-effectiveness analyses (incremental cost/relapse as well as hospitalization avoided). RESULTS: PP-LAI had the lowest rates for all negative events.  Respective outcomes for PP-LAI, RIS-LAI, HAL-LAI and oral-OLZ included relapse days (37.4, 51.2, 79.5, 78.0), Emergency Room visits (0.122, 0.168, 0.250, 0.242), hospitalizations (0.288, 0.394, 0.623, 0.615) and QALYs (0.8227, 0.7985, 0.7585, 0.7609). Expected costs were lowest for oral-OLZ (4447€), followed by 4474€ for HAL-LAI, 5326€ for PP-LAI, and 6223€ for RIS-LAI. HAL-LAI and RIS-LAI were both dominated and eliminated from further consideration. PP-LAI had an ICER of 14,247€/QALY gained over oral-OLZ, which was considerably below the NICE threshold (≈27,600€). In cost-effectiveness analyses, PP-LAI had ICERs of 1902€/relapse avoided and 2626€/hospitalization avoided. Model drivers were hospitalization for HAL-LAI (74%) and oral-OLZ (59%); for PP-LAI 49% was due to drug and 39% hospitalization and for RIS-LAI it was 44% drug and 44% hospitalization. CONCLUSIONS: PP-LAI is cost-effective in Portugal when compared with the customary treatments.