Nanomechanical resonators operating in vacuum are capable of detecting and weighing single biomolecules, but their application to the life sciences has been limited by viscous forces that impede their motion in liquid environments. A promising approach to avoid this problem, encapsulating the fluid within a mechanical resonator surrounded by vacuum, has not yet been tried with resonant sensors of mass less than ∼100 ng, despite predictions that devices with smaller effective mass will have proportionally finer mass resolution. Here, we fabricate and evaluate the performance of doubly clamped beam resonators that contain filled nanofluidic channels and have masses of less than 100 pg. These nanochannel resonators operate at frequencies on the order of 25 MHz and when filled with fluid have quality factors as high as 800, 2 orders of magnitude higher than that of resonators of comparable size and frequency operating in fluid. Fluid density measurements reveal a mass responsivity of 100 Hz/fg and a noise equivalent mass of 2 fg. Our analysis suggests that realistic improvements in the quality factor and frequency stability of nanochannel resonators would render these devices capable of sensing attogram masses from liquid. © 2010 American Chemical Society.