Objectives: The purpose of this prospective study was to evaluate the clinical behaviour of zirconia posterior fixed partial dentures (FPD) fabricated by Direct Ceramic Machining (DCM). Methods: 45 patients in need of 58 3- to 5- unit FPDs replacing molars and premolars were recruited for the present study. A recently developed system for the fabrication of zirconia frameworks was applied (DCM; ETH Zurich, Switzerland). The frameworks were ground out of porous pre-sintered TZP (tetragonal zirconia polycrystals) blanks by milling linearly enlarged copies of framework models. Subsequently they were sintered to full density, thereby shrinking to their final dimensions. The frameworks were veneered with porcelain and fixed with composite cement. At re-examination the following data were recorded at test and control-teeth: i.) fracture of framework/ veneering; ii.) probing pocket depth (PPD), probing attachment level (PAL), bleeding on probing (BoP), Plaque Index (PlI) and tooth mobility (TM); iii.) radiographical examination. Results: After a mean observation period of 42 (±7) months, 34 patients with 44 FPDs were re-examined (drop-outs: 11 patients / 13 FPD). No framework fractures were recorded. However, 7 FPDs had to be replaced due to technical (fracture of veneering, cementation error, loss of retention) or biological complications (endodontic problem, secondary caries, root fracture). The survival rate of the FPDs was 84%. Minor porcelain chipping was reported in 11% (n=5) of the bridges. 33% (n=28) of the anchors exhibited ill fitting margins. Secondary caries developed in 4% (n=3) of the cases. No statistically significant differences between test and control-teeth were found regarding PPD, PAL (p>0.5, paired t-test), BoP, PlI and TM (p>0.5, Friedman test). Conclusion: Zirconia frameworks made by DCM offer sufficient stability for the fabrication of 3- to 5-unit FPDs replacing posterior teeth. Complications resulting from marginal discrepancies need to be reduced by further refinements of the manufacturing techniques.