A thermopile device with sub-wavelength hole array (SHA) is numerically and experi-mentally investigated. The infrared absorbance (IRA) effect of SHAs in active area of the thermopile device is clearly analyzed by the finite-difference time-domain (FDTD) method. The prototypes are manufactured by the 0.35 µm 2P4M complementary metal-oxide-semiconductor micro-electro-mechanical-systems (CMOS-MEMS) process in Taiwan semiconductor manufacturing company (TSMC). The measurement results of those prototypes are similar to their simulation results. Based on the simulation technology, more sub-wavelength hole structural effects for IRA of such thermopile device are discussed. It is found from simulation results that the results of SHAs arranged in a hexagonal shape are significantly better than the results of SHAs arranged in a square and the infrared absorption efficiencies (IAEs) of specific asymmetric rectangle and elliptical hole structure arrays are higher than the relatively symmetric square and circular hole structure arrays. The overall best results are respectively up to 3.532 and 3.573 times higher than that without sub-wavelength structure at the target temperature of 60◦C when the minimum structure line width limit of the process is ignored. Obviously, the IRA can be enhanced when the SHAs are considered in active area of the thermopile device and the structural optimization of the SHAs is absolutely necessary.