Objective: This study evaluated the nanoleakage of two low-shrinkage composites in cavities with different cavity configuration factors (C-Factor). Materials and methods: Standardized class I cavities (4.5 mm width × 4.5 mm length × 1.8 mm depth) were prepared in ninety extracted human molars after removing occlusal enamel, with six different C-factors by applying nail polish to four walls (C1), three walls (C2), two walls adjacent to each other (C3a), two walls opposite to each other (C3b), one wall (C4), or no walls (C5). Cavities were equally divided and randomly assigned to one of the resin composites and their matching adhesive systems; Filtek Silorane/Silorane adhesive (SIL, 3M ESPE), Aelite LS/One-Step Plus (AL, BISCO) or Filtek Z250/Adper Single bond Plus (Z, 3M ESPE) that were used as a control. After 24 h storage in water, the specimens were sectioned, placed into 50% (w/v) ammoniacal silver nitrate solution for 24 h, exposed to photodeveloping solution and observed using SEM. Percentage distribution of metallic silver particles in the resin/dentin interface was calculated using digital image analysis software. Shrinkage stresses and stress rates of resin composites were measured continuously from start of light curing and up to 30 min using a Tensometer testing machine (NIST, Gaithersburg, MD). Data were analyzed by one-way ANOVA followed by a Tukey multiple comparisons test. (p < 0.05). Results: Increasing C-factor did not affect the nanoleakage of low shrinkage composites, meanwhile silver nitrate depositions were significantly increased in high C-factor cavities in the control group. Mean maximum shrinkage stresses results were 0.94 ± 0.1, 1.79 ± 0.18 and 2.14 ± 0.23 MPa for SIL, AL and Z, respectively. Conclusion: Using low shrinkage composites in cavities with high C-factor may be an alternative to avoid the deteriorating effect of increasing the C-factor on the bond of resin composite to dentin.