The aim of the present study was to develop floating matrix tablets of losartan potassium (LP). The floating matrix tablets of LP were prepared using different proportion of hydroxypropyl methyl cellulose (HPMC-K4M) and karaya gum. The prepared tablets were evaluated for various pre-compression & post-compression parameters, in vitro drug release and in vivo X-ray imaging in rabbits. All tablets showed excellent swelling and floating capabilities, short floating lag times and maintained controlled release for more than 16 h. The release of LP from optimized formulation F9 was found to be non-Fickian type. Gastric X-ray imaging of formulation F9 (containing LP/HPMC-K4M/karaya gum/microcrystalline cellulose/sodium bicarbonate/magnesium stearate/lactose) showed that the floating matrix tablet was continuously floating in the stomach region of the rabbit; hence, it could prolong the gastric retention time to more than 12 h. These results indicated that developed matrix tablets of LP could be successfully used for floating drug delivery system.