BACKGROUND: After acute ischemic stroke, it is uncertain whether the time of atrial fibrillation (AF) diagnosis (before or after stroke) or AF subtype (paroxysmal or permanent) modifies the treatment effect of early versus delayed direct oral anticoagulant (DOAC) initiation. METHODS: OPTIMAS was a randomized, parallel-group, open-label trial with blinded outcome assessment. Participants with acute ischemic stroke and AF were randomized 1:1 to early (within 4 days) or delayed (day 7-14) DOAC initiation. The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, and systemic arterial embolism. In this trial subgroup analysis, the prespecified subgroup of interest was time of AF diagnosis, classified as before or after the qualifying stroke. We also investigated AF subtype classified as persistent or paroxysmal. We fitted mixed effects logistic regression models with interaction terms between each subgroup and treatment allocation. We also investigated associations between AF time of diagnosis or subtype and outcomes using multivariable logistic regression. RESULTS: We included 3619 participants (mean age 78.0±9.9 years; 45.3% female). For AF diagnosed before stroke, 37 of 918 (4.0%) participants allocated to early DOAC had a primary outcome event versus 32 of 920 (3.5%) allocated to delayed DOAC, odds ratio, 1.17 (95% CI, 0.72-1.89), while for AF diagnosed after stroke the respective primary outcome rates were 22 of 895 (2.5%) and 27 of 886 (3.0%; odds ratio, 0.79 [95% CI, 0.45-1.40], Pinteraction=0.312). AF subtype did not modify the treatment effect, with odds ratios (95% CIs) for early versus late DOAC for persistent and paroxysmal AF of 1.06 (0.71-1.58) and 0.66 (0.25-1.72), respectively, Pinteraction=0.377. AF time of diagnosis was not associated with outcome events. Compared with paroxysmal AF, persistent AF was independently associated with an increased risk of the primary outcome (adjusted odds ratio, 2.10 [95% CI, 1.19-3.68]). CONCLUSIONS: We found no evidence that AF time of diagnosis or subtype modify the effects of early DOAC treatment. Persistent AF was independently associated with approximately double the risk of the primary outcome compared with paroxysmal AF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03759938.