Mesenchymal stem cells (MSCs) are pluripotent progenitor cells with the ability to generate cartilage, bone, muscle, tendon, ligament, and fat. However, recent evidence indicates that a major drawback of current cartilage- and intervertebral disc-tissue engineering is that human MSCs isolated from some arthritic patients (a clinically relevant source of stem cells) express type X collagen (a marker of chondrocyte hypertrophy associated with endochondral ossification) and osteogenic markers. Some studies have attempted to use growth factors to inhibit type X collagen expression, but none has addressed the possible effect of the chemical composition of the substratum on chondrocyte hypertrophy and osteogenesis. Here, we examine the growth and differentiation potential of human MSCs cultured on nitrogen (N)-rich plasma polymer layers (N-doped plasma-polymerized ethylene, containing up to 36% nitrogen; PPE:N). We show that PPE:N almost completely suppresses the expression not only of type X collagen, but also of osteogenic marker genes such as alkaline phosphatase, bone sialoprotein, and osteocalcin. In contrast, neither aggrecan nor type I collagen expression were significantly affected. These results indicate that PPE:N coatings may be suitable surfaces for inducing MSCs to a chondrocyte or disc-like phenotype for tissue engineering of cartilage or intervertebral discs, in which hypertrophy and osteogenesis are suppressed.