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Objectives We aimed to systematically summarise and quantify the empirical evidence on targeted interventions and their effects on various HIV prevention outcomes for long-distance truck drivers (LDTDs) globally.Design A systematic review and meta-analysis.Data sources We searched PubMed, PubMed Central (PMC), Cumulated Index to Nursing and Allied Health Literature (CINAHL), ProQuest Central, EBSCOhost, ScienceDirect, World Health Organisation (Global Index Medicus), Cochrane Library, Scientific Electronic Library Online (SCiELO), Japan Science and Technology Information Aggregator, Electronic (J-STAGE) and China National Knowledge Infrastructure (CNKI) up to 15 th May 2026.Eligibility criteria We included original peer-reviewed interventional studies involving LDTDs of either gender aged above 18 years and reporting findings on HIV prevention interventions from any part of the world. We excluded non-empirical publications like systematic reviews.Data extraction and synthesis We used a predesigned and piloted Microsoft Excel data extraction form to extract information on study details, characteristics of study participants, intervention characteristics, outcome measures and reported effect size measures. The general characteristics of the included studies were summarised using basic descriptive statistics like mean, frequencies and proportions. Where effect estimates for individual studies were missing, risk ratios (RR) were calculated from the proportions of the respective outcomes. Thereafter, we performed a random-effects meta-analysis using R. We performed a sensitivity analysis by excluding individual studies with outlier effect estimates and a subgroup analysis of studies with no high risk of bias. Where adequate data for meta-analysis were not reported, a narrative approach was used to synthesise the findings. The ROB 2 and ROBIN-1 Cochrane risk of bias assessment tools were used to assess the risk of bias for the randomised and non-randomised interventions, respectively. The certainty of evidence for the included studies was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.Results Of the 2076 records identified, 24 were included. Most of the included studies were conducted in the regions of SSA (50%, n=12) and Asia and the Pacific (37.50%, n=9). The frequently reported outcomes following targeted interventions were condom use, HIV-related knowledge, HIV testing and sexual risk behaviours. The pooled effect estimates showed that interventions on condom use had the most significant effect (RR=1.25; 95% CI, 1.09 to 1.44, p=0.002), followed by HIV-related knowledge (RR=1.24, 95% CI 1.13 to 1.36, p<0.001) and sexual risk behaviour reduction (RR=0.86; 95% CI, 0.74 to 0.99, p=0.042). Interventions on HIV testing showed a modest effect at follow-up, though not statistically significant (RR=1.14; 95% CI, 0.91 to 1.42, p=0.248). Significant heterogeneity was observed, indicating that the pooled effect estimates were not due to chance but other factors, such as intervention variations and sample size. Following sensitivity and subgroup analysis, we did not observe statistically significant changes in pooled effect estimates across most intervention outcomes. Based on the GRADE assessment, the certainty of evidence was predominantly very low, with only one study providing moderate-certainty evidence and three others providing low-certainty evidence.Conclusion Generally, most of the targeted interventions had significant effects on various HIV prevention outcomes and were randomised controlled trials, peer-led, outreach-based and adopted mobile health approaches. Thus, there is a need to upscale such interventions along transport corridors, as they had the most significant effects in promoting HIV prevention outcomes among LDTDs. However, the predominantly very low certainty of evidence based on the GRADE assessment limits confidence in the effect estimates reported in this study. Consequently, these findings should be interpreted with caution and confirmed through more rigorous, high-quality studies.PROSPERO Registration Number CRD42024505542