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Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line antiviral therapies for patients with chronic hepatitis B (CHB) and reduce the risk of disease progression and liver-related complications, as well as improve survival by effectively suppressing viral replication. Nevertheless, since the first publication in 2019 on a lower risk of hepatocellular carcinoma (HCC) in Korean patients receiving TDF than those receiving ETV, the topic has remained a hot and unsettled debate. Multiple studies and meta-analyses have yielded conflicting results. As HCC takes time to develop, studies are mainly observational to benefit from a larger sample size and longer follow-up that provides a higher statistical power to compare the two treatments. However, TDF was available to CHB patients a few years later than ETV in most countries, thus leading to a difference in follow-up duration. Moreover, despite studying the same topic, the difference in data sources and available parameters, inclusion and exclusion criteria, and use of statistical methods complicated the interpretation and comparison of the findings and contributed to between-study heterogeneity in meta-analyses. This review describes some caveats in interpreting and comparing the results from these observational studies and meta-analyses. Future studies should explore better designed observational studies with high-quality data sources, and aggregation of patient data in meta-analysis to tackle between-study heterogeneity.