The development of a vortex induced vibration (VIV) fatigue factor of safety (FoS) consistent with state-of-the-art industry design practice is cast within the coherent framework of reliability analysis. The proposed methodology consists of the following steps: (i) define the failure criteria or limit-state function (ii) setup a deterministic analysis model (iii) characterize the uncertainties involved in the problem (iv) propagate the uncertainties through the deterministic model and assess the probability of failure due to VIV fatigue and (v) calculate the FoS required to achieve a given failure probability. The proposed methodology is demonstrated by determining the FoS associated with using state-of-the-art VIV prediction models to attain varying reliability levels (probabilities of failure) in a hypothetical design scenario. Prediction uncertainty is based herein on measured flow and response data for several full-scale drilling risers working in the field. Results indicate that depending on the reliability level required of a particular design, different FoS than those that currently appear in guidance may be appropriate. Results also indicate the sensitivity of the FoS to the riser and prevailing current type, analysis program and input parameters, and accumulation of conservatism in aggregate versus single-event damage predictions.