BACKGROUND: Poor adherence to medications is a global public health concern with substantial health and cost implications, especially for chronic conditions. In the USA, poor adherence is estimated to cause 125,000 deaths and cost $US100 billion annually. The most successful adherence-promoting strategies that have been identified so far have moderate effect, are relatively costly, and raise availability, feasibility, and/or scalability issues. OBJECTIVE: The main objective of SIGMA (Study on Incentives for Glaucoma Medication Adherence) was to measure the effectiveness on medication adherence of a novel incentive strategy based on behavioral economics that we refer to as adherence-contingent rebates. These rebates offered patients a near-term benefit while leveraging loss aversion and regret and increasing the salience of adherence. METHODS: SIGMA is a 6-month randomized, controlled, open-label, single-center superiority trial with two parallel arms. A total of 100 non-adherent glaucoma patients from the Singapore National Eye Centre were randomized into intervention (adherence-contingent rebates) and usual care (no rebates) arms in a 1:1 ratio. The primary outcome was the mean change from baseline in percentage of adherent days at Month 6. The trial registration number is NCT02271269 and a detailed study protocol has been published elsewhere. FINDINGS: We found that participants who were offered adherence-contingent rebates were adherent to all their medications on 73.1% of the days after 6 months, which is 12.2 percentage points (p = 0.027) higher than in those not receiving the rebates after controlling for baseline differences. This better behavioral outcome was achieved by rebates averaging 8.07 Singapore dollars ($US5.94 as of 2 November 2017) per month during the intervention period. CONCLUSION: This study shows that simultaneously leveraging several insights from behavioral economics can significantly improve medication adherence rates. The relatively low cost of the rebates and significant health and cost implications of medication non-adherence suggest that this strategy has the potential to cost-effectively improve health outcomes for many conditions.