To evaluate the cost-effectiveness of canagliflozin in dual therapy as add-on to metformin compared to sitagliptin and in triple therapy as add-on to metformin (MET) and sulfonylurea (SU) compared to sitagliptin. The IMS CORE Diabetes Model was used to evaluate the cost-effectiveness of canagliflozin 100 mg and 300 mg versus sitagliptin 100 mg using data from both clinical trials and network meta-analysis, combined with Portuguese-specific data when available. The perspective of the analysis is societal in accordance with Guidelines for Economic Drug Evaluation Studies from INFARMED. The cost-effectiveness analyses indicate that canagliflozin (100 mg and 300 mg weighted average 65: 35) is cost-saving and results in higher QALYs in comparison with sitagliptin 100 mg in dual therapy as add-on to metformin and in triple therapy as add-on to MET plus SU. In dual therapy as add-on to MET, canagliflozin (100 mg and 300 mg weighted average 65: 35) has an average cost saving of 24 € and an average QALY gain of 0.036. In triple therapy as add-on to MET+SU, canagliflozin (100 mg and 300 mg weighted average 65: 35) has an average cost saving of 171 € and an average QALY gain of 0.033. Probabilistic analysis suggests a likelihood of 59% of canagliflozin being cost-effective compared to sitagliptin in dual therapy and 59% in triple therapy at a willingness-to-pay of 30,000 € per gained QALY. Sensitivity analyses showed that canagliflozin is cost-effective also from a payer perspective and even when the time horizon, which is 30 years in the base case, is reduced to 10 years. Canagliflozin 100 mg and 300 mg will be a cost-effective alternative to sitagliptin in both dual and triple therapies, as add-on to MET or as add-on to MET+SU, respectively.