The health gains and costs resulting from using different caries detection strategies might not only depend on the accuracy of the used method but also the treatment emanating from its use in different populations. We compared combinations of visual-tactile, radiographic, or laser-fluorescence-based detection methods with 1 of 3 treatments (non-, micro-, and invasive treatment) initiated at different cutoffs (treating all or only dentinal lesions) in populations with low or high caries prevalence. A Markov model was constructed to follow an occlusal surface in a permanent molar in an initially 12-y-old male German patient over his lifetime. Prevalence data and transition probabilities were extracted from the literature, while validity parameters of different methods were synthesized or obtained from systematic reviews. Microsimulations were performed to analyze the model, assuming a German health care setting and a mixed public-private payer perspective. Radiographic and fluorescence-based methods led to more overtreatments, especially in populations with low prevalence. For the latter, combining visual-tactile or radiographic detection with microinvasive treatment retained teeth longest (mean 66 y) at lowest costs (329 and 332 Euro, respectively), while combining radiographic or fluorescence-based detections with invasive treatment was the least cost-effective (<60 y, >700 Euro). In populations with high prevalence, combining radiographic detection with microinvasive treatment was most cost-effective (63 y, 528 Euro), while sensitive detection methods combined with invasive treatments were again the least cost-effective (<59 y, >690 Euro). The suitability of detection methods differed significantly between populations, and the cost-effectiveness was greatly influenced by the treatment initiated after lesion detection. The accuracy of a detection method relative to a "gold standard" did not automatically convey into better health or reduced costs. Detection methods should be evaluated not only against their criterion validity but also the long-term effects resulting from their use in different populations.