Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide [1], [2]. Most CRC cases are sporadic and non-inherited, influenced by the local gut environment and the accumulation of mutations and epigenetic changes. Besides genetic predisposition as a risk for CRC, nutrients such as vitamins have also been linked to CRC [3], [4].

Riboflavin (RF, also known as vitamin B2), one of the B vitamins, is an essential component of two major coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These coenzymes play major roles in energy production, cellular function, growth, and metabolism as important components of intracellular biochemistry [5], [6]. It has been suggested that riboflavin assists in preventing DNA damage triggered by a variety of carcinogens by acting as a coenzyme with several different cytochrome P450 enzymes [7]. Interestingly, riboflavin deficiency has been implicated in inhibition of tumor growth in animal models and cell experiments [8]. Studies showed that high-dose riboflavin supplementation played an important role in promoting the proliferation, invasion, and migration of cancer cells [9]. Inhibiting mitochondrial respiration by targeting flavin-containing enzymes also eliminated cancer stem cells (CSCs) [10]. These findings have suggested a potential role for riboflavin in colorectal carcinogenesis and metastasis, but academic conclusions have differed from those of epidemiological studies.

The results of the association between riboflavin and cancer prevention or treatment are limited, and study findings are conflicting [11], [12], [13], [14]. Observational studies on the relationship between riboflavin intake and colorectal cancer risk did not produce consistent results. A few cohort studies and meta-analyses found that total intake of riboflavin from both foods and supplements were associated with a lower risk of colorectal cancer [15], [16], [17], [18]. Also, there are null findings from individual cohort studies [12], [19], [20], [21], [22], [23] and case–control studies [24], [25], [26], [27], [28], [29], [30], [31]. For instance, a cohort study on a large population of current, former, and never smokers who were followed for up to 12 years found no association between riboflavin intake and colorectal cancer risk in any group [32]. A cross-sectional study on esophageal squamous-cell carcinoma demonstrated that decreased riboflavin was a prognostic factor for poor overall survival (HR = 1.91 (1.19–3.07), p = 0.007) [33].

We therefore performed this study to evaluate the association between serum riboflavin levels and the risk of sporadic CRC. Further, we evaluated whether the association varies according to several CRC risk factors, including sex, age, history of polyps, life style, multivitamin status, drug treatment, and concomitant diseases. This study may contribute to a better understanding of the experimental and observational findings regarding the association between serum riboflavin and CRC risk.