Background: Under normal physiological conditions, the spin-lattice relaxation rate (R1) in blood is influenced by many factors, including hematocrit, field strength, and the paramagnetic effects of deoxyhemoglobin and dissolved oxygen. In addition, techniques such as oxygen-enhanced magnetic resonance imaging (MRI) require high fractions of inspired oxygen to induce hyperoxia, which complicates the R1 signal further. A quantitative model relating total blood oxygen content to R1 could help explain these effects. Purpose: To propose and assess a general model to estimate the R1 of blood, accounting for hematocrit, SO 2 , PO 2 , and B0 under both normal physiological and hyperoxic conditions. Study Type: Mathematical modeling. Population: One hundred and twenty-six published values of R1 from phantoms and animal models. Field Strength/Sequence: 5-8.45 T. Assessment: We propose a two-compartment nonlinear model to calculate R1 as a function of hematocrit, PO 2 , and B0. The Akaike Information Criterion (AIC) was used to select the best-performing model with the fewest parameters. A previous model of R1 as a function of hematocrit, SO 2 , and B0 has been proposed by Hales et al, and our work builds upon this work to make the model applicable under hyperoxic conditions (SO 2 > 0.99). Models were assessed using the AIC, mean squared error (MSE), coefficient of determination (R 2 ), and Bland-Altman analysis. The effect of volume fraction constants W RBC and W plasma was assessed by the SD of resulting R1. The range of the model was determined by the maximum and minimum B0, hematocrit, SO 2 , and PO 2 of the literature data points. Statistical Tests: Bland-Altman, AIC, MSE, coefficient of determination (R 2 ), SD. Results: The model estimates agreed well with the literature values of R1 of blood (R 2 = 0.93, MSE = 0.0013 s À2 ), and its performance was consistent across the range of parameters: B0 = 1.5-8.45 T, SO 2 = 0.40-1, PO 2 = 30-700 mmHg. Data Conclusion: Using the results from this model, we have quantified and explained the contradictory decrease in R1 reported in oxygen-enhanced MRI and oxygen-delivery experiments. Level of Evidence: 3 Technical Efficacy: Stage 1