Purpose: The purpose of this preliminary prospective study was to evaluate the clinical outcome of crown-retained and inlay-retained fixed partial dentures (FPDs) made from a new lithium-disilicate glass-ceramic (IPS e.max Press, Ivoclar Vivadent). Materials and Methods: Eighty-one 3-unit FPDs were placed in 68 patients. The FPDs replaced teeth in the anterior (8%) and posterior region (92%). All teeth were prepared according to a standardized protocol. The size of the proximal connector of the FPDs was 12 mm2 (anterior) or 16 mm2 (posterior), respectively. Crown-retained FPDs were cemented either with glass ionomer (n = 20) or resin composite (n = 16), while all inlay-retained FPDs (n = 45) were cemented with resin composite. Initial follow-up was performed at 6 and 12 months and annually thereafter. Results: The mean observation periods were 48 months (for crown-retained FPDs) and 37 months (for inlay-retained FPDs). None of the crown-retained FPDs failed during the observation period, while 6 inlay-retained FPDs (13%) had to be replaced. Six cases failed because of debonding (n = 3) or a combination of debonding and fracture (n = 3). During the observation period, 2 patients died and the status of another 5 patients is unknown. The 4-year survival rate according to Kaplan-Meier was 100% for crown-retained FPDs and 89% for inlay-retained FPDs. The differences between the groups were statistically significant. Conclusion: Crown-retained 3-unit FPDs made from a new glass-ceramic have a significantly better outcome up to 5 years than inlay-retained 3-unit FPDs over the observation period.