The criteria for evaluating research studies often include large sample size. It is assumed that studies with large sample sizes are more meaningful than those that include a fewer number of participants. This chapter explores biases associated with the traditional application of null hypothesis testing. Statisticians now challenge the idea that retention of the null hypothesis signifies that a treatment is not effective. A finding associated with an exact probability value of p = 0.049 is not meaningfully different from one in which p = 0.051. Yet the interpretation of these two studies can be dramatically different, including the likelihood of publication. Large studies are not necessarily more accurate or less biased. In fact, biases in sampling strategy are amplified in studies with large sample sizes. These problems are of increasing concern in the era of big data and the analysis of electronic health records. Studies that are overpowered (because of very large sample sizes) are capable of identifying statistically significant differences that are of no clinical importance.