Histocompatibility (HL-A) phenotypes of 44 unrelated white patients from the greater Boston area with amyotrophic lateral sclerosis (ALS) and 200 white controls were compared. In the overall ALS group, an increased frequency of HL-A3 was noted (43% vs 25%, P less than .05). Thirty-eight patients had rapidly progressive disease; among this group the HL-A3 incidence was 50% (P less than .005). Six patients had slowly progressive disease, none had HL-A3, and five had HL-A12. The HL-A antigens may link with disease severity in ALS.