Omega-3 fatty acids (n-3 FA) supplementation has been widely used regardless the initial FA composition of the studied population. In this work we compared the red blood cell FA (RBC-FA) composition in healthy and different diseased populations at baseline and show how this affects the incorporation of n-3 FA supplementation in ICU-trauma patients. Blood was drawn from Healthy (H, n = 22), Psoriasis (P, n = 13), Cancer(C, n = 81), Geriatric (G, n = 49), Social-phobia (SP, n = 27) and ICU-trauma (T, n = 40) patients before n-3 FA supplementation. For the T group blood was also drawn 8 days after receiving a formula with 4.1 g/L EPA and 5.5 g/L GLA (Oxepa, Abbott). RBC-FA was assessed by gas chromatography and the percentage of each FA was calculated in relation to the total identified FAs. Baseline RBC-FA profile was significantly different between groups (p < 0.0001) with subjects in the healthy group having higher n-3 FA status. H and SP showed the highest content in total n-3 FA (11.89 ± 0.22% H vs 7.45 ± 0.26% T) and EPA (1.61 ± 0.03% H vs 0.41 ± 0.13% P). DHA was higher in C and H than in the other groups (6.15 ± 0.15% C vs 4.32 ± 0.11% T). ARA was highest in C (16.04 ± 0.20% C vs 14.85 ± 0.22% H) and comparable in the rest of the groups. The n-6/n-3 ratio was lowest for H and highest for T (2.75 ± 0.07 vs 4.96 ± 0.13). Moreover, we showed that for the T group, the treatment-associated changes in the n-3 content are dependent on the initial n-3 FA status, since a negative correlation between the baseline omega 3 index (EPA + DHA) and its change after supplementation was found (p = 0.002, r2 = 0.219). We conclude that RBC-FA profile should be evaluated and considered individually for each patient or groups before generalized supplementation schemes, strengthening the concept of personalized medicine.