In clinical research, comparisons of the results from experimental and control groups are often encountered. The two-sample t-test (also called independent samples t-test) and the paired t-test are probably the most widely used tests in statistics for the comparison of mean values between two samples. However, confusion exists with regard to the use of the two test methods, resulting in their inappropriate use. In this paper, we discuss the differences and similarities between these two t-tests. Three examples are used to illustrate the calculation procedures of the two-sample t-test and paired t-test.