Objective: To estimate the adjusted relative risk (RR) of administrative grant disruption faced by first-time and mechanism-first principal investigators (PIs) during the 2025 National Institutes of Health (NIH) grant disruptions. Design: Retrospective cohort study linking NIH RePORTER data to a publicly curated registry of grants disrupted in 2025. Setting: All NIH active research grants in fiscal years 2024 to 2025. Participants: 80,976 active projects: 4,961 disrupted during the wave that peaked in May 2025, 76,015 non-disrupted controls. Main outcome measures: Adjusted RR of disruption by two pre-specified first-time PI constructs: absolute first-time PI (no prior NIH grant) and mechanism-first PI (no prior NIH grant with the same activity code). Modified Poisson regression with institution-clustered standard errors adjusted for project, institutional, and geographic covariates. A pre-specified fiscal year 2024 common-anchor analysis addressed year-of-disruption confounding. Results: Of 4,961 disrupted grants, 237 (4.8%) had an absolute first-time PI and 396 (8.0%) had a mechanism-first PI. After adjustment, absolute first-time PIs faced 77% elevated risk of disruption (RR 1.77, 95% CI 1.34 to 2.32) and mechanism-first PIs faced 57% elevated risk (RR 1.57, 1.16 to 2.11). Under the common-anchor analysis, the absolute first-time effect attenuated to RR 1.22 (0.95 to 1.58); the mechanism-first effect persisted (RR 1.48, 1.07 to 2.06). The elevated risk was concentrated in research-mechanism grants (RR 1.78, 1.26 to 2.52) and was robust across 8 of 9 pre-specified sensitivity analyses. The Track A start-time construct, which asks whether the disrupted project was the PI's debut grant, yielded null estimates (RR 0.98, 0.93 to 1.04), with any effect concentrated entirely in newly started projects. Conclusions: First-time and mechanism-first PIs faced disproportionately elevated risk of disruption during the 2025 NIH wave, concentrated in research-mechanism grants and robust to year-confounding-free identification. The relevant exposure was being early-career at the moment of administrative action, not at project initiation. The findings have direct implications for workforce equity in US biomedical research.