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Interleukin-18 (<i>IL-18</i>) is a multi-functional immuno-mediator in the development and progression of many types of infectious and inflammatory diseases. In this study, we evaluated the contribution of <i>IL-18</i> genotypes to renal cell carcinoma (RCC) in Taiwan via the genotyping of <i>IL-18</i> -656 (A/C), -607 (A/C), and -137 (G/C). Moreover, we analyzed their interactions with smoking, alcohol drinking, hypertension, and diabetes status. The results showed an association of the AC and CC genotypes of <i>IL-18</i> &#8722;607 with a significant decrease in the risk of RCC compared with the AA genotype (odds ratio (OR) = 0.44 and 0.35, 95% confidence interval (CI) = 0.27&#8211;0.72 and 0.18&#8211;0.66, <i>p</i> = 0.0008 and 0.0010, respectively). Furthermore, a significantly lower frequency of the C allele at -607 was observed in the RCC group (35.3% vs. 49.8%; OR = 0.53; 95% CI = 0.35&#8211;0.71, <i>p</i> = 0.0003). However, <i>IL-18</i> -656 and -137 did not exhibit a likewise differential distribution of these genotypes between the control and case groups. Stratifying the population according to smoking, alcohol drinking, hypertension, and diabetes status revealed a different distribution of <i>IL-18</i> -607 genotypes among non-smokers, non-drinkers, and patients without diabetes, but not among smokers, drinkers, or patients with diabetes. These findings suggest that <i>IL-18</i> -607 genotypes may play a role in the etiology and progression of RCC in Taiwan and may serve as a useful biomarker for early detection.