The effect of roughness on the tribological behavior of the prosthetic pair ultra high molecular weight polyethylene (UHMWPE)/TiN coated stainless steel was investigated. Standard and polished TiN coated stainless steel pins were tested against either standard or smooth UHMWPE disks. Hanks' Balanced Salt Solution (HBSS) and bovine serum albumin (BSA) solution in HBSS were used as lubricants. Friction and wear were determined using a pin-on-disk apparatus and the wear mechanisms were investigated through optical microscopy, scanning electron microscopy, and atomic force microscopy. The results showed that the decrease in the roughness led to a reduction of the friction coefficient and of the wear rate of UHMWPE. However, the most important effect was achieved through the decrease in the roughness of the hard TiN counterface while keeping the standard UHMWPE surface. If BSA was added to HBSS, a strong decrease of both the friction coefficient and the polymeric wear was observed independently of the roughness of both the TiN and the polyethylene surfaces. Abrasive and fatigue wear mechanisms are proposed to interpret the experimental results.