Schizophrenia is a chronic disorder that requires long-term treatment with antipsychotic medication to minimize relapse and provide clinical benefit to patients. For patients with schizophrenia, non-adherence to medication is a risk factor for relapse and re-hospitalization. Long-acting Injectable (LAI) formulations of atypical antipsychotics provide constant medication delivery and the potential for improved adherence. The objective of this study is to assess the cost-effectiveness of paliperidone palmitate (PP) versus risperidone long acting injectable (RLAI), olanzapine (OP) and quetiapine (QP). A Markov decision analytic model was developed to simulate multi-episode patients transitioning through different states on monthly basis over a 5 year time horizon from the perspective of the Colombian Health System. Probability of relapse, level of adherence, side effects, utilities and treatment discontinuation were derived from scientific literature. Only direct costs were considered as medications, laboratory tests, relapses and adverse events by using national tariffs and prices from Ministry of Health medication database. Outcomes were measured as relapses rate and Quality Adjusted Life Years (QALY). Discount rate 3%, exchange rate (1 USD = 1,794 COP) and threshold considered 3xPIB per capita (USD 20,066 / QALY). Total costs (USD): PP (13,338), RLAI (12,635), OP (11,481) and QP (13,247). Hospitalization relapses costs (USD): PP (3,276), RLAI (3,341), OP (4,881) and QP (6,840). QALY: PP (3.09), RLAI (3.00), OP (2.93) and QP (2.87). Relapses rate: PP (1.35), RLAI (1.38), OP (2.01) and QP (2.81). Incremental Cost Utility Ratios (ICUR: USD / QALY): PP vs. RLAI (4,517), PP vs. OP (6,713) and PP vs. QP (230). Considering a willingness to pay of USD 20,066 per QALY, the incremental cost of PP versus other alternatives could be compensated by its incremental benefits in terms of relapses avoided and QALY gained. From Health Care Provider perspective, PP demonstrates savings in terms of less hospital setting relapsing costs.