The aim of the study was to evaluate the clinical performance of the nanofiller resin composite Filtek Supreme (3M ESPE) vs the conventional fine hybrid resin composite Tetric Ceram (Ivoclar Vivadent) in stress-bearing posterior cavities. In accordance with a split mouth study design, 50 patients (35.7+/-11.3 years) received at least one pair of Filtek Supreme and Tetric Ceram restorations in each of two comparable class II cavities. To obtain comparability, the adhesive Scotchbond 1 was used for all the restorations. After 2 years, the restorations (total number 112) were scored according to the Ryge criteria. After 2 years (recall rate 100%), the results (%) of the Ryge evaluation for the two groups Filtek Supreme/Tetric Ceram were marginal adaptation: Alfa 96/96, Bravo 2/2, Charlie 2/0, and Delta 0/2; anatomic form: Alfa 98/98, Bravo 0/0, and Charlie 2/2; secondary caries: Alfa 100/100 and Bravo 0/0; marginal discoloration: Alfa 98/100, Bravo 2/0, and Charlie 0/0; surface: Romeo 95/95, Sierra 4/4, Tango 0/0, and Victor 2/2; and color match: Oscar 46/57, Alfa 50/39, Bravo 2/4, and Charlie 2/0. One Tetric Ceram and one Filtek Supreme restoration showed fractures that needed restorative intervention. No severe postoperative sensitivities were reported within the observation period. All restored teeth remained vital; the integrity of all the teeth was scored Alfa. After 2 years, no statistically significant differences (Wilcoxon-Mann-Whitney test) was found between the two restorative materials investigated. Therefore, Filtek Supreme, based on a new nanofiller technology, has proved efficaciousness for clinical use in stress-bearing posterior cavities.