BACKGROUND: α OBJECTIVE: To characterize the influence of SERPINA1 variation on asthma severity. METHODS: DNA samples from 847 non-Hispanic whites and 446 African Americans from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1,955 individuals with asthma and α MEASUREMENTS AND MAIN RESULTS: In whites, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related healthcare utilization. This was attributed to PI type Z heterozygotes (MZ, N=11) who had a higher frequency of ED visits (6 [54.5%] MZ heterozygotes, OR=7.60, 95%CI=1.71-39.7, p=0.010), hospitalization (5 [45.5%], OR=16.1, 95%CI=2.64-150.4, p=0.0050) in the past year, and lifetime ICU admissions (6 [54.5%], OR=12.5, 95%CI=2.44-75.6, p=0.0032) compared to 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, 15 [10.3%] ICU admission). SERPINA1 variant-ever smoking interactions in African Americans for ED visits (p=0.069) related to four of six compound heterozygotes reporting an ED visit. In CCHS, α CONCLUSIONS: SERPINA1 variation and α