This study reports on the formulation of doxycycline HCL in an ion activated in situ gelling delivery system and its implications for the treatment of periodontal disease. The system is based on the use of alginate as the gelling agent and hydroxypropyl methylcellulose (HPMC) as a viscosity enhancing agent. The ion activated gelling mechanism in this system is based on the concept of interaction with the divalent calcium ions present in the gingival crevicular fluid (GCF). The gelling capacity of the prepared formulations was assessed visually and by investigating their rheological behavior upon mixing with human blood serum since it has the same composition as the GCF. The rheological behavior of all formulations was not affected by incorporation of the drug. In vitro release studies showed that the alginate/HPMC mixture, upon gelling after mixing with serum, can sustain the release of doxycycline HCL for an extended period of time which was more than 12 days. These results indicated that this system can be used as an in situ gelling local delivery system for the treatment of periodontal disease. (C) 2009 Wiley Periodicals, Inc. J Appl Polym Sci 115:811-816, 2010