Our findings show that copy number loss of FHIT is associated with lymph node metastasis (LNM) and suggest that the down-regulation of Fhit indicates poor prognosis in early oral squamous cell carcinoma (OSCC). The purpose of this study was to identify alterations in genetic markers related to LNM in early OSCC. Genome-wide copy number alterations were analyzed in 14 early OSCCs with (n = 7) or without (n = 7) cervical LNM using 180K array-comparative genomic hybridization. To explore the prognostic implications of the most significantly associated genetic alteration with cervical LNM, immunohistochemical analysis was conducted in 30 OSCCs. A total of 11 recurrently altered regions (RARs) were identified in the 14 OSCC cases. Six RARs on chromosomes 3p26-3p14, 5q22, and 9p21 were found to be significantly more common in early OSCC with LNM (p < 0.05). Among these, loss of 3p14.2 (where the FHIT gene is located) was the most frequent (five of seven patients with LNM, and none of seven without LNM), and most significantly associated with cervical LNM (p = 0.005). Fhit immunohistochemical staining of 30 OSCCs showed that Fhit negativity was associated with cervical LNM (p = 0.032) and poor disease-specific survival (p = 0.045).