Background <p>Mobile phone dependence (MPD) is a serious public health concern in schools. To advance cross-cultural understanding of MPD, this study examined factor structure, measurement invariance, and latent mean differences of the mobile phone dependence questionnaire (MPDQ) across mainland Chinese and Hong Kong adolescents.</p> Methods <p>The present cross-sectional study included a total of 918 middle school students (588 boys and 310 girls; <i>M</i>_age = 13.58, <i>SD</i> = 1.46), comprising 367 adolescents from two Shenzhen schools and 551 adolescents from three Hong Kong schools. Confirmatory factor analysis, measurement invariance test, latent mean comparisons, and multidimensional item response theory analysis were employed for data analyses.</p> Results <p>The three-factor structure of the MPDQ, proposed by previous research conducted in Hong Kong adolescents, was also supported in mainland Chinese adolescents. Configural, partial metric, and partial scalar cross-cultural measurement invariance were all achieved. Mainland Chinese adolescents reported higher scores on all MPD factors than their Hong Kong counterparts.</p> Conclusions <p>The findings highlight the cross-cultural similarities and differences of MPD among adolescents in mainland China and Hong Kong. The MPDQ is culturally sensitive to measure MPD in both regions, while certain items may need further cultural adaptation. Moreover, Hong Kong adolescents demonstrated more disordered thoughts and behaviors associated with MPD than mainland Chinese adolescents. Implications for using the MPDQ for assessing and understanding the MPD from diverse cultural backgrounds are discussed.</p> Clinical trial number <p>Not applicable.</p>