This study aimed to explore the prognostic value of LMX1B mRNA expression and the methylation of its CpG sites in patients with laryngeal squamous cell carcinoma (LSCC). An in-silicon analysis was performed using data from the cancer genome atlas (TCGA)-Head and Neck Squamous Carcinoma (HNSC). After screening, 112 LSCC and 10 adjacent normal tissues were identified as eligible samples for analysis. Results showed that LMX1B expression was significantly upregulated in the cancer tissues (p < 0.01) and was an independent prognostic indicator in terms of OS (HR: 1.233, 95%CI: 1.082–1.405, p = 0.002) and RFS (HR: 1.200, 95%CI: 1.002–1.438, p = 0.048). By examining the methylation profile of 55 CpG sites in LMX1B locus, we found that the promoter methylation status was irrelevant to LMX1B expression. In comparison, LMX1B expression was generally positively correlated with gene body methylation. Among the gene body CpG sites, cg13600622 methylation showed a better predictive value than LMX1B expression in terms of OS (HR: 12.363, 95%CI: 1.076–142.033, p = 0.043), while cg14204784 methylation was a better marker of shorter RFS (HR: 12.363, 95%CI: 1.076–142.033, p = 0.043). Among the known downstream genes of LMX1B, only NR4A2 expression showed a moderately negative correlation (Pearson’s r = −0.54) with it in LSCC tissues. However, this correlation was inconsistent with previous publications those reported a positive correlation between them. Based on these findings, we infer that upregulated LMX1B mRNA expression had an independent prognostic value in LSCC patients. Increased gene body methylation might be an important mechanism of its upregulation. Among the gene body CpG sites, cg13600622 and cg14204784 methylation level might be better prognostic markers than LMX1B mRNA expression in terms of OS and RFS respectively.