A quantitative structure-activity relationship (QSAR) investigation of a set of 23 substituted 2,4-diamino-5-benzylpyrimidines spanning an activity range of 1.8 log (1/C) units was carried out using molecular shape analysis (MSA). C is the molar concentration necessary for 50% inhibition of bovine liver dihydrofolate reductase (DHFR). The "active" shape of these compounds was deduced by comparing the change in conformational state to the activity of four compounds outside the data base described above. A correlation equation, and analogous in descriptor form to those developed earlier for DHFR inhibition by substituted, 2,4-diaminotriazines and -quinazolines, was constructed. The correlations coefficient, r, was 0.931 and the standard deviation of fit, s, was 0.137. The results suggest that these pyrimidines bind to DHFR with shape features different from both the triazines and quinazolines. It is postulated from the "active" shape of the pyrimidines that it is preferable to substitute at the meta position of the benzyl ring rather than at the para position.