The largest portion of the cost for asthma healthcare is due to hospitalizations. Improved methods of healthcare delivery for patients with asthma are needed to prevent readmissions. From 1996 to 1999, 96 adult subjects (predominantly young African American women) hospitalized with an asthma exacerbation, who had a history of frequent healthcare use, were randomized to an asthma nurse specialist intervention (n = 50) or a usual care group (n = 46) for 6 months. Our aim was to decrease rates of readmissions within 6 months of hospital discharge, to reduce cost, and to improve health-related quality of life. Our results demonstrate a 60% reduction in total hospitalizations (31 readmissions in the intervention group and 71 in the control group, p = 0.04), with no significant change in emergency department visits. Readmissions for asthma were reduced by 54% (21 vs. 42 in the control group; p = 0.04). We found a marked reduction in lost work or school days: 246 versus 1040 days in the control group (p = 0.02). The intervention resulted in a substantial reduction in direct and indirect healthcare costs, saving US dollars 6462 per patient (p = 0.03). A brief intervention program focusing on high healthcare users with asthma can result in improved asthma control and reduced hospital use with substantial cost savings.