ABSTRACTTo understand the molecular evolution of human parainfluenza virus type 2 (HPIV2), 21 Hemagglutinin-Neuraminidase (HN) gene sequences covering seven Chinese provinces in 2011 and 2017 to 2021 were combined with 90 published HN sequences worldwide for phylogenetic analysis. The result showed that global HPIV2 could be classified into two distinct clusters (I and II), five lineages (IA to IIE), and four sublineages (IB1 and 2, and IIE1 and 2). The minimum genetic distances between different clusters and lineages were 0.049 and 0.014, respectively. In the last decade, one lineage (IID) and three sublineages (IB1, IB2, and IIE1) have been cocirculating in China, with the sublineages IB2 and IIE1 dominating, while sublineages IB1 and IIE1 are dominant globally. In addition, the spread of HPIV2 had relative spatial clustering, and sublineage IB2 has only been detected in China thus far. The overall evolution rate of HPIV2 was relatively low, on the order of 10−4substitutions/site/year, except for sublineage IB2 at 10−3substitutions/site/year. Furthermore, human–animal transmission was observed, suggesting that the HPIV2 might have jumped out of animal reservoirs in approximately 1922, the predicted time of a common ancestor. The entire HN protein was under purifying/negative selection, and the specific amino acid changes and two novel N-glycosylation sites (N316 and N517) in sublineages IB1, IB2, and IIE1 were mostly located in the globular head region of the HN protein. In this study, preliminary evolutionary characteristics of HPIV2 based on the HN gene were obtained, increasing the recognition of the evolution and adaptation of HPIV2.IMPORTANCEThe phylogenetic analysis showed that global HPIV2 could be classified into two distinct clusters (I and II) and five lineages (IA to IIE) with at least 0.049 and 0.014 genetic distances between clusters and lineages, respectively. Furthermore, lineages IB and IIE could be further divided into two sublineages (IB1-2 and IIE1-2). All China sequences belong to one lineage and three sublineages (IB1, IB2, IID, and IIE1), among which sublineages IB2 and IIE1 are predominant and cocirculating in China, while sublineages IB1 and IIE1 are dominant globally. The overall evolution rate of HPIV2 is on the order of 10−4substitutions/site/year, with the highest rate of 2.18 × 10−3for sublineage IB2. The entire HN protein is under purifying/negative selection, and the specific amino acid substitutions and two novel N-glycosylation sites (N316 and N517) in sublineages IB1, IB2, and IIE1 are mostly located in the globular head region of the HN protein.