We report molecular dynamics (MD) simulation evidence of a new family of two-dimensional (2D) clathrate hydrates. Particular attention is placed on the effect of size and hydrophilicity of guest-molecule on the formation of 2D clathrate hydrates. Among MD simulations undertaken, spontaneous formation of bilayer (BL) clathrate hydrates in nanoslits are found with five different hydrophobic guest molecules, namely, ethane (C2H6), ethene (C2H4), allene (C3H4), carbon dioxide (CO2) and hydrogen (H2) molecules, respectively. Our simulations suggest that the host cages in water framework are likely BL-hexagonal cages with single occupancy for H2, or BL-heptagonal cages for CO2. With further increase of guest size, the host cages for C2H6, C2H4, and C3H4 are BL-octagonal cages with single occupancy, and their long molecular axis tends to be normal to the surface of clathrate hydrates. In addition, for hydrophilic guest molecules such as NH3 and H2S which can form strong hydrogen bonds with water, we find that most guest molecules can preferentially displace water molecules from lattice sites of water framework, instead of being separately trapped within water cages. Structural analogy between the 2D and 3D clathrates enlightens us to predict stability of several bulk gas hydrates, namely, “ethane clathrate III”, “CH4 ice-i” and “H2 ice-i”. Our findings not only can enrich clathrate structures in the hydrate family but also may improve understanding of the hydrate formation in microporous media.