The aim of this study was to examine the safety and physiochemical properties of a new biodegradable and biocompatible collagen based drug delivery system(COL-DDS) implanted into the anterior chamber in a rabbit eye. The physiochemical and ultra-structural differences of COL-DDS were evaluated with and without crosslinking with carboxymethylcellulose(CMC). The in vitro and in vivo assays of the collagen released and the residual collagen content revealed an expected inverse relationship between the collagen release rate and the swelling ratio of the COL-DDS, which might be exploited for the controlled presentation and release of carriers. Fifty New Zealand albino rabbits(20 eyes) undergoing phacoemulsification were divided into two groups receiving normal saline eye drops(group A) and a COL-DDS implanted subconjunctivally into the anterior chamber(group B). Collagen/CMC crosslinked COL-DDS showed a significantly higher level of reduction in the swelling ratios compared with the non crosslinked COL-DDS(two-factor ANOVA, p<0.0001). Crosslinking as well as the collagen content had a significant effect on the volume changes(two-factor ANOVA, p=0.001). The mean aqueous humor collagen level in groups A and B was 0.0121 ?g/ml and 25.964 ?g/ml, respectively. Collagen was still detectable in the aqueous humor after the DDS had completely dissolved at 12 weeks in group B. The slit-lamp biomicroscopy revealed no inflammatory signs in the anterior chamber. The conjunctiva, cornea, iris, ciliary body and retina remained intact, and no significant toxic reactions were observed. The implantation of a COL-DDS into the anterior chamber of the experimental animals maintained a similar collagen level in the aqueous humor for a relatively long period of time. This highlights the potential for the prevention of anterior chamber disease with minimal toxic and side effects. Therefore, a long acting DDS requiring only a weekly subcutaneous administration appears to be useful in a clinical setting.