Steady-state and transient variations in frictional force observed in tribological experiments of mesothelial tissues sliding in lubricant were analyzed with a mathematical model to test the hypothesis that such phenomena are manifestations of elastohydrodynamic lubrication and, importantly, do not require physical contact between the sliding surfaces. The model incorporates three phenomena characteristic of elastohydrodynamic lubrication: thinning of the liquid layer between sliding surfaces under a normal load (“squeeze-out”), thickening of the liquid layer due to hydrodynamic pumping, and smoothing of the elastic surfaces caused by hydrodynamic pressure gradients. Observations in soft mesothelial tissues sliding in lubricant showed variations in steady state friction with velocity, load, and lubricant viscosity. In non-steady sliding, the decay rate of frictional transients at the start of rotation varied with velocity, the amplitudes of these transients varied with the preceding periods without rotation, and frictional force varied during sinusoidal sliding. Model simulations were qualitatively similar to experimental results, supporting these mechanisms. Higher lubricant viscosity increased lubricating layer thickness and lowered friction at low speeds and increased friction at high speeds, supporting hydrodynamic pumping. We conclude that the frictional variations seen with sliding mesothelial tissues are consistent with elastohydrodynamic lubrication without contact between the sliding surfaces.