Today, it is common practice to carry out fatigue assessments of ship structures using direct calculation procedures. Many numerical codes are available for these types of analyses. They could yield different values in a fatigue life prediction due to the different degrees of complexity as well as the large number of uncertainties in the computation of the ship’s response. In this investigation, a comparative study is carried out on a Panamax container ship in oblique waves using different typical direct calculation methods. The results of fatigue life prediction using these methods are compared with results obtained from full-scale measurements. It is found that the nonlinear time-domain method shows the best agreement with the full-scale measurements, and therefore, it is recommended to be used in fatigue predictions.