Non-canonical mismatches account for about half of all base pairs in RNA. One common non-canonical motif is a 2x2 internal loop or tandem mismatch, which occurs when adjacent mismatches are situated between two Watson-Crick base pairs. In a database of 955 RNA sequences, known secondary structures (determined by comparative sequence analysis) contained 899 2x2 internal loops. Out of these loops, only 24% have been studied thermodynamically. In addition, out of the 30 most frequently occurring 2x2 loops, thermodynamic data has only been determined for five of these loops. This limited set of naturally occurring 2x2 loops is the basis for the model used by RNA StructureŽ(Mathews, et. al., 1999), a computer program downloaded by over 12,000 users, to predict the thermodynamics and secondary structure of 2x2 loops in RNA. As a result, the current model contains many assumptions and may be an oversimplification of the model. In this research, thermodynamic data was gathered for the 30 most frequently occurring 2x2 loops in nature and a new model, which uses thermodynamic data from 69% of 2x2 loops in the database, is proposed.