We previously reported enhanced proliferation of smooth muscle cells on the combined exposure of HIV proteins and cocaine leading to the development of HIV-pulmonary arterial hypertension. Here, we attempt to comprehensively understand the interactions between long noncoding RNAs (lncRNAs), mRNAs and micro-RNAs (miRNAs) to determine their role in smooth muscle hyperplasia. Differential expression of lncRNAs, mRNAs and miRNAs were obtained by microarray and small-RNA sequencing from HPASMCs treated with and without cocaine and/or HIV-Tat. LncRNA to mRNA associations were conjectured by analyzing their genomic proximity and by interrogating their association to vascular diseases and cancer co-expression patterns reported in the relevant databases. Neuro-active ligand receptor signaling, Ras signaling and PI3-Akt pathway were among the top pathways enriched in either differentially expressed mRNAs or mRNAs associated to lncRNAs. HPASMC with combined exposure to cocaine and Tat (C + T) vs control identified the following top lncRNA-mRNA pairs, ENST00000495536-HOXB13, T216482-CBL, ENST00000602736-GDF7, and, TCONS_00020413-RND1. Many of the down-regulated miRNAs in the HPASMCs treated with C + T were found to be anti-proliferative and targets of up-regulated lncRNAs targeting up-regulated mRNAs, including down-regulation of miR-185, -491 and up-regulation of corresponding ENST00000585387. Specific knock down of the selected lncRNAs highlighted the importance of non-coding RNAs in smooth muscle hyperplasia.