The production of tissue plasminogen activator (tPA) in various micro-filtration hollow fiber (MFHF) bioreactors for mammalian cell culture was compared. When the surface area of the bioreactor was increased 3-fold, tPA production per m(2) decreased 30%. Changing the angle of the medium distributor at the inlet of the hollow fiber cartridge increased the tPA production per m(2) by 15%. tPA production reached a maximum at 20 d, but then decreased gradually. In order to maintain the tPA production over a long period, a cartridge whose surface area was reduced by 20% by decreasing the number of hollow fibers was utilized. tPA was produced stably, and the tPA production per m(2) was 238 mg/d/m(2). Cumulative tPA production for 50 d reached 19 g, and was almost equal to that with the previous cartridge. It was concluded that the MFHF bioreactor can be scaled up if a uniform and sufficient supply of oxygen is achieved and good physiological conditions for mammalian cells are maintained.