| S&T | Directorate for Science and Technology |
| SABER | Statistical Analysis Battery for Epidemiological Research |
| SACGHS | Secretary's Advisory Committee on Genetics, Health and Society |
| SACGT | Secretary's Advisory Committee on Genetic Testing (absorbed by SACGHS) |
| SACX | Secretary's Advisory Committee on Xenotransplantation (defunct; see Wayback Machine) |
| SAIF | Saving Associate Insurance Fund (merged into DIF) |
| SAMHSA | Substance Abuse and Mental Health Services Administration |
| SAO | Smithsonian Astrophysical Observatory |
| SAOP | Senior Agency Officials for Privacy |
| SAVE | Systematic Alien Verification for Entitlement |
| SBA | Small Business Administration |
| SBIR | Small Business Innovation Research |
| SBRP | Superfund Basic Research Program (access forbidden 07/10; see About SBRP) |
| SCF | Strengthening Communities Fund |
| SCHIP | State Children's Health Insurance Program |
| SciDAC | Scientific Discovery through Advanced Computing |
| SCNGO | Strategic Center for Natural Gas and Oil |
| SCOTUS | Supreme Court of the United States |
| SDP | Sustainable Development Partnerships |
| SDWIS | Safe Drinking Water Information System |
| SEC | Securities and Exchange Commission | Space Environment Center (changed to SWPC) |
| SEDAC | Socioeconomic Data and Applications Center |
| SEDS | State Energy Data System |
| SEER | Surveillance, Epidemiology, and End Results |
| SERC | Smithsonian Environmental Research Center |
| SES | Senior Executive Service |
| SETS | Statistical Export and Tabulation System |
| SEVIS | Student and Exchange Visitor Information System |
| SEVP | Student and Exchange Visitor Program |
| SFMNP | Senior Farmers' Market Nutrition Program |
| SFS | Scholarship for Service |
| SFSP | Summer Food Service Program |
| SGLI | Servicemembers' Group Life Insurance |
| S/GWI | Office of Global Women's Issues |
| SHARE Initiative | Safety, Health and Return-to-Employment |
| SI | Smithsonian Institution |
| SIC | Standard Industrial Classification |
| SIES | Strategic Industries & Economic Security |
| SIGTARP | Office of the Special Inspector General for the Troubled Asset Relief Program |
| SITES | Smithsonian Institution Traveling Exhibition Service |
| SJI | State Justice Institute |
| SLAC | Stanford Linear Accelerator Center |
| SLAITS | State and Local Area Integrated Telephone Survey |
| SLHIE | State-level Health Information Exchange |
| SLSDC | Saint Lawrence Seaway Development Corporation |
| SMART | Office of Sex Offender Sentencing, Monitoring, Apprehending, Registering, and Tracking |
| SNAP | Supplemental Nutrition Assistance Program |
| SNL | Sandia National Laboratories |
| SOL | Office of the Solicitor |
|
| SPC | Storm Prediction Center |
| SPR | Strategic Petroleum Reserve |
| SRP | Superfund Research Program |
| SRS | Savannah River Site |
| SS | Secret Service |
| SSA | Social Security Administration |
| SSAB | Social Security Advisory Board |
| SSBG | Social Services Block Grant Program |
| SSI | Supplemental Security Income Program |
| SSS | Selective Service System |
| STAG | State and Tribal Assistance Grant Programs |
| STAR | Center for Satellite Applications and Research |
| Stat. | United States Statutes at Large |
| STB | Surface Transportation Board |
| STEWARDS | Sustaining the Earth's Watersheds, Agricultural Research Data System |
| STI | Scientific and Technical Information |
| STRI | Smithsonian Tropical Research Institute |
| SuDoc | Superintendent of Documents |
| S/WCI | Office of War Crimes Issues |
| SWPC | Space Weather Prediction Center |
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