Background: During recent years, microRNAs (Greek: micros = small; miRNA) have become more important. miRNAs are highly conserved, noncoding, single-stranded RNA molecules 17–28 nucleotide in length. Secreted by tumor cells, miRNAs regulate many biological processes and are also involved in chemoresistance. Classical forms of cancer treatment lead to miRNA release. Which miRNAs are correlated to head and neck squamous cell carcinomas (HNSCC) and their chemoresistance to paclitaxel remains unknown. Objectives: Identification of miRNAs expressed in HNSCC and elucidation of those involved in conferring chemoresistance to paclitaxel. Materials and methods: To identify changes in gene expression, HNSCC cell lines were treated with 10 µM paclitaxel for 48 h and analyzed by microarray analysis. Thereafter, changed in expression of single miRNAs (miR221*, miR222 and miR222*) following paclitaxel treatment were analyzed using a quantitative real-time polymerase chain reaction (qRT-PCR). Results: Under treatment with paclitaxel, miRNAs were released. The dominant change is upregulation of MIR222 gene expression. Regulation of miR222* expression under paclitaxel treatment seems to be different in human papillomavirus (HPV)-negative and HPV-positive HNSCC cell lines. Conclusion: Expression of mirR221/222 is correlated to cell cycle regulation, carcinogenesis, and chemoresistance. Detailed knowledge of the molecular mechanisms and effects of miRNAs is important for identifying miRNAs as cancer markers, as well as for increasing the efficiency of cancer therapeutics.