OBJECTIVES To conduct a systematic review of cost-effectiveness, cost-utility and cost-benefit studies of new inhibitors of DPP-4 for diabetes treatment versus other antidiabetics. METHODS We searched the CRD York, NICE Health Technology Assessment, Tufts CEA Registry, and MEDLINE (PubMed) databases, and grey literature through 2014 to identify cost-effectiveness, cost-utility and cost-benefit studies of new inhibitors of DPP-4 versus other antidiabetics for diabetes treatment. Three investigators independently reviewed all potentially relevant titles and abstracts (1^st screening), and subsequently screened full-text articles (2^nd screening), according to pre-established inclusion criteria. We restricted our sample to studies with a lifetime or near-lifetime horizon, and adopting either a societal or a healthcare perspective. The studies should be available as a full-text publication and published in English, French, Spanish, or Portuguese language. A critical appraisal of the methodology and reporting was performed using the 35item version of the BMJ checklist. RESULTS A total of 57 studies were identified. From these, 17 studies were accepted after the 1^st screening, of which 11 were accepted after the 2^nd screening. All selected studies consisted in cost-utility analyses. Most studies were based on a single randomized trial per therapy. Saxagliptin was assessed in 6 studies, Sitagliptin in 4, and vildagliptin in 1. Liraglutide was cost-effective versus sitagliptin as second line therapy (ranged from 12,164 to 27,289€/QALY across countries). Saxagliptin (ranged from 771 to 10,065 €/QALY across countries), Sitagliptin (ranged from 5,949 €/QALY to 20,350 €/QALY across countries) and vildagliptin (ICER of 9,072 €/ QALY in Portugal) were cost-effective versus sulfonylureas as second line therapy. CONCLUSIONS According to commonly accepted thresholds, there is consistent evidence about the cost-effectiveness of DDP-4 inhibitors as second line therapy for diabetes type 2. Though, more evidence (including head-to-head) is necessary to define which DDP-4 inhibitor is the most cost-effective.