Background: Depression imposes a substantial burden on society. In view of the economic burden of depression, studies evaluating depression treatment increasingly incorporate a cost-utility analysis. Outcomes of these analyses are used by decision makers to prioritize healthcare. Although generic preference-based instruments have been recommended for measuring utility, depression research often uses a disease-specific method, based on depression-free days (DFD), to measure utilities. Aims of the Study: The objective of this study was to compare utility measurement techniques in the context of a randomized controlled trial. In particular, we studied the agreement between QALYs measured with the EuroQol (EQ-5D), the Short Form 6D (SF-6D), and the DFD method, using the EQ-5D as the reference method. We also studied whether the use of different techniques leads to different conclusions for decision makers. Methods: Data were derived from the Depression in Elderly with Long-Term Afflictions (DELTA) study. This randomized controlled trial was designed to study the effectiveness and cost-effectiveness of a minimal psychological intervention for chronically ill patients with co-occurring minor or mild to moderate major depression. The EQ-5D, SF-6D and Beck Depression Inventory (to estimate DFDs) were assessed at baseline, and at three, six and twelve months after baseline. Results: Poor agreement was found between the EQ-5D and DFD (Kendall's Tau: 0.33; ICC: 0.21 (95% CI:-0.07-0.45)) and moderate agreement between the EQ-5D and SF-6D (Kendall's Tau: 0.60; ICC: 0.47 (95% CI: 0.36-0.57)). The incremental cost-utility ratio led to similar conclusions for decision makers across techniques. Discussion: In conclusion, utilities from the disease-specific DFD method should not be compared directly with utilities derived from the EQ-5D. Although a disease-specific method might yield similar cost-utility ratios as generic instruments, generic instruments remain the preferred option for prioritizing healthcare. Limitations of this study include the presence of minor depression and chronic illnesses in our study population. Implications: Generic instruments remain preferred for cost-utility analyses, especially when results are used to prioritize healthcare. If the DFD method is a way forward, further research is required to validate utility weights assigned to the DFDs