Several studies have reported improved sepsis outcomes when certain preadmission antihypertensive drugs, namely, calcium channel blockers (CCBs), are used. This study aims to determine whether preadmission antihypertensive drug use, especially angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), is associated with decreased total hospital mortality in sepsis. This study was conducted using the unique database of a sepsis cohort from the National Health Insurance Research Database in Taiwan. Frequency matching for age and sex between preadmission antihypertensive drug users (study cohort) and nonusers (comparison cohort) was conducted. The primary outcome was total hospital mortality. Logistic regression analyses were performed to calculate the odds ratios (ORs) of important variables. Further joint effect analyses were carried out to examine the impacts of different combinations of antihypertensive drugs. A total of 33,213 sepsis antihypertensive drug use patients were retrieved as the study cohort, and an equal number of matched sepsis patients who did not use antihypertensive drugs were identified as the comparison cohort. The study cohort had a higher incidence rate of being diagnosed with septic shock compared with the comparison cohort (4.36%-2.31%, P < 0.001) and a higher rate of total hospital mortality (38.42%-24.57%, P < 0.001). In the septic shock condition, preadmission antihypertensive drug use was associated with a decreased adjusted OR (OR = 0.66, 95% confidence interval [CI], 0.55-0.80) for total hospital mortality, which was not observed for the nonseptic shock condition. Compared with antihypertensive drug nonusers, both ACEI and ARB users had decreased adjusted ORs for total hospital mortality in sepsis (adjusted OR = 0.93, 95% CI, 0.88-0.98 and adjusted OR = 0.85, 95% CI, 0.81-0.90); however, CCB, beta-blocker, and diuretic users did not. In the septic shock condition, ACEI, ARB, CCB, and beta-blocker users all had decreased ORs for total hospital mortality. Joint effect analysis showed ACEI use, except in combination with diuretics, to be associated with a decreased adjusted OR for total hospital mortality in sepsis. Similar results were observed for ARB users. Preadmission ACEI or ARB use is associated with a decreased risk of total hospital mortality, regardless of a nonshock or septic shock condition.