Randomized controlled trials (RCTs) are widely recognized as the gold standard approach for evaluating the effectiveness of an intervention in health care or clinical practices. In a health care setting, RCT is used to assess whether an intervention is effective in improving health status or health service delivery system. The success of the trial depends not only on how well it has been designed, implemented, or analyzed but also on patient, institutional, or existing health policy–related factors. Therefore, the principal investigator faces many challenges with regard to study design, implementation, data collection, and building relationships with service providers and patients. This case study summarizes practical issues that should be considered while undertaking a cluster RCT. It is based on the findings of our recently completed trial on isoniazid preventive therapy (IPT) uptake among people living with HIV (PLHIV) in a limited-resource setting in Nepal. The objective of this trial was to assess whether community-based intervention improves initiation (primary outcome) and completion (secondary outcome) rates of IPT among newly registered PLHIV in 11 antiretroviral therapy (ART) centers of Sudurpashchim (English translation of which would be “Far Western”) province, and this province was initially named as Province Number 7. We designed a cluster RCT. The ART centers were randomly assigned to intervention centers or control centers (with allocation ratio 6:5). Community- and home-based care teams were recruited and mobilized in the intervention centers. The ART incharges assigned them a set of activities for promotion of IPT.