A series of 2-(2,6-dihalophenyl)-3-(substituted pyrimidinyl)-1,3-thiazolidin-4-ones were designed on the prediction of quantitative structure-activity relationship (QSAR) studies, synthesized, and evaluated as HIV-1 reverse transcriptase inhibitors. Our attempts in correlating the identified molecular surface features related properties for modeling the HIV-1 RT inhibitory activity resulted in some statistically significant QSAR models with good predictive ability. The results showed that compounds 4m and 4n were highly active in inhibiting HIV-1 replication with EC(50) values in the range of 22-28 nM in MT-4 as well as in CEM cells with selectivity indexes of >10,000. The derived models collectively suggest that the compounds should be compact without bulky substitution on its peripheries for better HIV-1 RT inhibitory activity. These models also indicate a preference for hydrophobic compounds to obtain good HIV-1 RT inhibitory activity.