The Omega-3 Index (O3I) is the percent of EPA and DHA of total erythrocyte membrane fatty acids1. Various factors: sex, age, genetics, and body mass index influence individual O3I2. There is need for tailored study designs to ensure participants reach the 8 - 11% O3I optimal target. Most studies have relied on fixed dose and duration intervention assuming ≥8% O3I target will be reached. This study aimed to: (1) determine the duration required for daily 1 g DHA supplementation to reach 8% O3I in healthy individuals consuming vegan/vegetarian (VGN/VTN) or non-restrictive (NR) diets and (2) identify the factors that explain the variability of response. Healthy study participants (n = 58, 18 male, 39 female, 1 other, mean age 36.4 ± 15.1 years, BMI 24.9 ± 3.9 kg/m2) consuming VGN/VTN (n = 20) and NR (n = 38) volunteered for this open-label pilot clinical trial (#ACTRN12625000253404). Height, weight, waist circumference, age, and gender data were collected at baseline (week 0). Finger-prick blood was collected at weeks 0, 4, and 8 and sent to Fatty acid labs, Victoria to measure O3I3. Stepwise linear regression was used to model response variability. At week 0, mean ± standard deviation O3I in NR was 6.1% ± 1.1% compared to 5.2% ± 1.6% in VGN/VTN (p = 0.005). At week 4, O3I was 8.1% ± 1.1% in NR (49% reached 8% O3I) and 7.4% ± 1.4% in VGN/VTN (20% reached 8% O3I) (p = 0.036). At week 8, O3I was 8.3% ± 0.8% (14% reached 8% O3I) in NR and 7.5% ± 0.7% in VGN/VTN (15% reached 8% O3I) (p = 0.027). In both diet groups, there was a large increase in O3I from 0 - 4 weeks, expressed as ΔO3I(W0-W4), approximately 2% (2.1% ± 1.0% in NR and 2.1% ± 0.8% in VGN/VTN) but very little increase from 4 - 8 weeks, ΔO3I(W4-W8), approximately 0.1% (0.9% ± 0.8% in NR and 0.6% ± 0.6% in VGN/VTN). The rate of change in O3I between diet groups was not significant. ΔO3I(W0-W4) response in whole cohort showed 20% variability (r2 = 0.20) is explained by baseline O3I (13%, p = 0.003) and waist circumference (7%, p = 0.016). Furthermore, baseline O3I (28%, p < 0.001) and diet group (4%, p = 0.057) explained 35% variability (r2 = 0.35) in ΔO3I(W0-W8) response. The O3I increased in the first 4 weeks of DHA supplementation, then appeared to plateau and baseline O3I was the main factor that influenced the response. Overall, 63% of participants in NR and 35% of participants in VGN/VTN reached 8% O3I within 8 weeks. A higher dose and/or longer duration of DHA supplementation to reach target 8% O3I may be warranted, especially for VGN/VTN diet group.