Abstract: This study aimed to assess the association of Tumor Necrosis Factor (TNF-α) Locus-308 variant, TNF-α and Interleukin (IL-10) Cytokine with the risk of silicosis and its progress in Indonesian cement factory workers, There is an urgent need to explore the determining factors other than exposure since silicosis is chronic progressive and life threatening but remains found, though much industrial hygiene effort has been made. This study population was 6,069 workers registered during 31 December 1990 to 31 December 2003. First, prospective study with Nested Case Control design was conducted on 336 workers in 2003, ten years later the progression of silicosis was assessed in 2013. The result showed proportion of the genetic variation on TNF-α on Locus -308 in Indonesia was significantly (p = 0.02) higher on silicosis (13.45%) than nonsilicosis (5.45%) but lower than silicosis in Africa and US miners, since susceptibility loci might vary in different ethnic groups. The sign and symptoms remained as simple silicosis after ten years; The TNF-α:IL-10 ratio >1 was a risk factor in silicosis; the ratio of TNF-α:IL-10 >1 caused a rapid decline of lung function compare to ratio <1, the decline was chronic progressive during ten years yet not causing significant dyspnea among the cases. Further studies with enlarged sample size are needed. The study concluded, the genetic variation on TNF-α gene locus -308 was a risk factor of silicosis in Indonesia cement factory. Its role is indirect, but through mechanism of controlling the blood Cytokine level ratio of TNF-α toward IL-10.