TDP-43 has recently been described as the major component of the inclusions found in the brain of patients with a variety of neurodegenerative diseases, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. TDP-43 is a ubiquitous protein whose specific functions are probably crucial to establishing its pathogenic role. Apart from its involvement in transcription, splicing and mRNA stability, TDP-43 has also been described as a Drosha-associated protein. However, our knowledge of the role of TDP-43 in the microRNA (miRNA) synthesis pathway is limited to the association mentioned above. Here we report for the first time which changes occur in the total miRNA population following TDP-43 knockdown in culture cells. In particular, we have observed that let-7b and miR-663 expression levels are down- and upregulated, respectively. Interestingly, both miRNAs are capable of binding directly to TDP-43 in different positions: within the miRNA sequence itself (let-7b) or in the hairpin precursor (miR-663). Using microarray data and real-time PCR we have also identified several candidate transcripts whose expression levels are selectively affected by these TDP-43–miRNA interactions.