Sulfobetaine-modified polymethylmethacrylate (PMMA) systems were created by physically entrapping the zwitterionic species on the PMMA surface. The presence of the sulfobetaine molecules on these surfaces were verified by ATR-FTIR and SEM-EDAX analysis, while wettability of the films was investigated by dynamic contact angle measurements. The short-term (4 h) adhesion of two bacterial species (gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa) on these surfaces were studied. Mouse RAW 264.7 macrophage cells were used to assess the cell adhesion and inflammatory response by quantifying the expression levels of proinflammatory cytokines namely TNFα and IL1β by measuring their mRNA profiles in the cells using real-time polymerase chain reaction (RT-PCR) normalized to the house keeping gene GAPDH. Whilst mouse L-929 fibroblast cells were used to assess the propensity for the materials to support fibroblast cell adhesion. A decrease in the adhesion of S. aureus by 63% and P. aeruginosa by 49% was observed on sulfobetaine modified PMMA films after 4 h. In all the cases, sulfobetaine modified PMMA films reduced cellular adhesion events (P < 0.05) with respect to the base materials, which could be linked to the reduced protein adsorption observed on these surfaces. The cellular inflammatory response was suppressed on sulfobetaine modified substrates as expression levels of pro-inflammatory cytokines (TNFα and IL1β) was found to be up regulated on bare PMMA, while it was significantly lower on sulfobetaine modified PMMA (P < 0.001). Thus the sulfobetaine entrapment process can be applied on polymethylmethacrylate in order to achieve low biointeractions and reduced inflammatory host responses for various biomedical and biotechnological applications. © 2009 Springer Science+Business Media, LLC.