We tackle the essential protein discovery problem from a significance testing perspective. More precisely, the essential protein discovery problem is formulated as a multiple hypothesis testing problem, where the null hypothesis is that each protein is not an essential protein. To quantify the statistical significance of each protein, we present a p-value calculation method in which both the degree and the local clustering coefficient are used as the test statistic and the Erdos-Renyi model is employed as the random graph model. After calculating the p-value for each protein, the false discovery rate is used as the error rate in the multiple testing correction procedure. Our significance-based essential protein discovery method is named as SigEP, which is tested on both simulated networks and real PPI networks. The experimental results show that our method is able to achieve better performance than those competing algorithms.