Subacute bacterial endocarditis (SBE) was invariably a fatal disease in the pre-penicillin era. The availability of sulfonamide antibiotics beginning in the mid-1930s raised hopes that they would be effective in SBE. Unfortunately, except in rare instances, they were not. This paper reviews the clinical experience with sulfonamides in the pre-penicillin period in treating patients with SBE. It presents in detail the case of Pasquale Imperato, who died from the disease at the age of 72 years on 30 November 1942. In so doing, it focuses on the medical management measures then available to treat patients with SBE and on the inevitable course of the illness once it began. Also discussed is the relationship of acute rheumatic fever and its sequela, rheumatic heart disease, to predisposing people to SBE and possible genetic factors. The well-known case of Alfred S. Reinhart, a Harvard Medical School student who died from SBE in 1931 and who kept a detailed chronicle of his disease, is also discussed and contrasted with Pasquale Imperato's case.