Purpose of Review <p>Long-term nucleos (t)ide analogue (NAs) treatment is usually required to maintain viral suppression in patients with chronic hepatitis B (CHB), with raising concerns on the long-term safety of NA therapy. In this review, we comprehensively summarized the current evidence on the long-term safety of NA therapy, with a particular focus on the first-line NAs (entecavir [ETV], tenofovir disoproxil fumarate [TDF], and tenofovir alafenamide [TAF]).</p> Recent Findings <p>The first-line NAs have no (TDF, TAF) or very low (ETV) viral resistance rates in treatment-naïve patients. ETV is associated with birth defects in animal studies. TDF is associated with a small risk renal and bone toxicity, primarily in older and higher risk patients. TAF has favorable renal and bone safety as compared to TDF, while its impact on lipid metabolism warrants attention. Although extremely rare, severe lactic acidosis can occur during NA treatment.</p> Summary <p>Long-term therapy with NAs is generally very safe, with potential risk of birth defects with ETV based on animal studies, potential viral resistance with ETV (rare if treatment-naïve and significant if prior lamivudine exposure/resistance), potential renal and bone mineral density adverse effects with TDF, lipid metabolism dysfunction with TAF, and rare but potentially severe lactic acidosis.</p>