As the most important, expensive component of a hydrokinetic turbine system, the composite turbine blade must achieve a long operating life (10–20 years). The investigation of fatigue life for the composite turbine blade is essential when designing a cost-effective hydrokinetic composite turbine system. A reliability-based fatigue life analysis methodology was developed for a medium-scale, horizontal axis, hydrokinetic turbine blade. Finite element method, coupled with the blade element momentum theory, was used to find the stress response on the turbine blade. The fatigue behavior of the blade was studied in stress-critical zones. A metamodel was constructed for the stress response according to simulations at specified design points. Accounting for uncertainties in material properties and the material S–N curve, the reliability analysis method was employed to estimate the fatigue life distribution of the hydrokinetic turbine blade. The effect of river velocity models on the fatigue life of turbine blades was also studied. The fatigue life of the composite blade was sensitive to composite material properties. Transverse strain E22 is particularly dominant which is related to the matrix cracking as the fatigue failure mode. The statistical distribution of S–N data implies a significant dependence of fatigue life on composite S–N data.