The scale-up of Streptomyces hygroscopicus subsp. aureolacrimosus in submerged culture and the production of milbemycin, a 16-membered macrolide pesticidal antibiotic, are described. The primary scare-up of a dissolved oxygen (DO)-stat culture to 12 000 dm(3) failed for milbemycin production, when only agitation was used for DO control. whenever production deteriorated in a plant-scale fermenter, several symptoms (such as morphological changes) were observed, termed SUDS (Scale-Up-Deteriorated production Syndrome). A series of experiments generating SUDS intentionally, replacing agitation-increasing with aeration-increasing operation, and examining internal pressure or temperature effects indicated alternative DO control procedures to prevent SUDS. Among these procedures investigated, a sole procedure resulted in successful scare-up to plant-scale (6000 and 12 000 dm(3)). In the control procedure, these control variables were employed in the order of internal pressure, aeration, agitation and culture temperature.