Objective To explore the efficacy and safety of conversion therapy for advanced hepatocellular carcinoma (HCC) with macrovascular invasion. Methods A total of 149 patients with advanced HCC with macrovascular invasion who were treated at our hospital from Jul. 2019 to Jun. 2021 were enrolled. All patients received systemic therapy combined with local therapy, and were assigned to conversion therapy group (n＝42) and non-conversion therapy group (n＝107) according to whether they ultimately underwent surgical treatment. The long-term prognosis and adverse reactions of these patients after conversion therapy were analyzed. Results The median event-free survival of 149 patients was 15.5 months, and the median overall survival had not been reached. The median event-free survival in the conversion therapy and non-conversion therapy groups were 19.8 months and 10.7 months, respectively, with the median overall survival being not reached and 28.2 months, respectively. Multifactor Cox regression analysis showed that conversion therapy was a protective factor for overall survival (hazard ratio ［HR］ ＝0.125, 95% confidence interval ［CI］ 0.016-0.966), but not for event-free survival. The 1-year and 2-year overall survival rates of the conversion therapy and non-conversion therapy groups were 100.0%, 96.4% and 72.1%, 53.4%, respectively, and the difference in survival curves between the 2 groups was statistically significant (P＝0.003). The 1-year and 2-year event-free survival rates were 77.5%, 33.8% and 47.3%, 31.5%, respectively. There was no significant difference in survival curves between the 2 groups (P＝0.070). The differences of the overall incidences of targeted and immunotherapy-related adverse reactions in the conversion therapy group and non-conversion therapy group (66.7% ［28/42］ vs 72.0% ［77/107］, P＝0.524) and the incidences of grade Ⅲ to Ⅳ adverse reactions (23.8% ［10/42］ vs 27.1% ［29/107］, P＝0.681), were not statistically significant. Conclusion For patients with advanced HCC with macrovascular invasion, conversion therapy can significantly improve the prognosis without serious adverse reactions.