Peritoneal dialysis (PD) is a standard form of life-saving renal replacement therapy for patients with end stage renal disease. Long term use of PD fluid (PDF) leads, however, to injury of mesothelial cells that line the peritoneal cavity, ultimately resulting in fibrosis and failure of peritoneum. The PDF-induced injury of immortalized mesothelial cells was described to be associated with activation of the enzyme glycogen synthase kinase - 3 (GSK-3). The inhibition of GSK-3 through lithium, applied as lithium chloride (LiCl), has been shown to be related to attenuation of PDF-induced cell injury. Although activation of GSK-3 in primary human peritoneal mesothelial cells (HPMC) could not be observed within the short term exposure to PDF (0.5 h), these cells were protected by LiCl. To identify the entire set of LiCl-affected targets that might be involved in observed cytoprotection, in this study, we investigated the PDF- and LiCl-altered transcriptome and proteome of HPMC exposed to icodextrin-based PDF (Baxter Extraneal®) without or with LiCl. The transcriptome was investigated with gene expression microarrays (Affymetrix U219) and the proteome was analyzed using 2D gel-based approach. The pathways affected by PDF were determined using the PANTHER database. Cell injury triggered by PDF was associated with differential expression of 855 transcripts (linked to 601 gene names) whereas on the protein level 92 spots were altered. Pathway analysis performed using transcripts affected by Extraneal showed an overrepresentation of 6 pathways: oxidative stress response, CCKR signaling, VEGF signaling, GnRH receptor signaling, angiogenesis, and PDGF signaling. PDF supplemented with LiCl attenuated the Extraneal-induced cell injury. Furthermore, LiCl altered the expression of 1482 transcripts (linked to 1003 gene names) and the abundance of 104 protein spots. Counter-regulation analysis revealed that 62 genes affected by Extraneal were attenuated by LiCl. These genes were defined as markers of the observed cytoprotection. Eight of them were involved in overrepresented pathways and therefore they might be considered as particularly promising candidates able to attenuate PDF-affected pathways. With proteomics, we confirmed the LiCl-dependent attenuation of the following chaperons involved in overrepresented pathways: heat shock protein 72 (Hsp72) encoded by HSPA1A/HPSA1B, already described in PD research as well as -crystallin chain (CRYAB) encoded by CRYAB not yet investigated in PD, reported, however, in stress research. CRYAB is indeed known to mediate the fibrosis-related processes; thus, its role in induction of peritoneal fibrosis needs to be evaluated in ongoing in-vivo studies.