Lithium (Li) is commonly used in the treatment of bipolar disorder (BD). However, the molecular mechanism of its action is not completely understood. MicroRNAs (miRNAs), a class of small RNA species are recognized as important regulators in post-transcription gene expression. To explore the role of miRNAs in Li's action, we quantitatively analysed the expression patterns of 13 miRNAs in 20 lymphoblastoid cell lines (LCLs) with or without Li treatment in culture. Using paired t statistics in the analysis, we identified significant changes in seven of the 13 miRNAs tested in LCLs sampled at treatment day 4 (p<0.05). Four of the seven significant miRNAs, miR-34a, miR-152, miR-155, and miR-221 consistently changed expression in the same LCLs at a longer treatment time-point, day 16 (Bonferroni p<0.05). Interestingly, miR-221 and miR-34a also changed expression in rat hippocampus in response to Li treatment (Zhou et al.2008), although in the opposite direction. We focused on the predicted target mRNAs of miR-221 and miR-34a, and identified 29 and ten targets that were strongly and inversely correlated to expression with the two miRNAs, respectively. Our results suggest that miRNAs are excellent candidates for the study of the molecular basis of Li's treatment action in cell systems such as lymphocytes given limited access to the human brain.