Background <p>Coinfection with schistosomiasis and tuberculosis (TB) remains common in endemic settings across Sub-Saharan Africa. Despite this coendemicity, studies evaluating the therapeutic efficacy and safety of praziquantel in patients receiving rifampicin-based anti-TB drugs are lacking. We investigated the efficacy and safety of a single 40&#xa0;mg/kg dose of praziquantel in schistosomiasis–TB coinfected patients undergoing rifampicin-based anti-TB therapy.</p> Methods <p>A prospective efficacy and safety study was conducted among 159 patients with schistosomiasis-TB coinfection treated with single 40&#xa0;mg/kg dose praziquantel. A pre-tested questionnaire was used to gather both sociodemographic and clinical data. A single stool sample was collected, and duplicate Kato Katz smears prepared for detection of <i>Schistosoma mansoni</i> both at baseline and follow-up. Efficacy of the drug was assessed by both parasitological cure and egg reduction rates (ERR) at 3-week’ post-treatment. Adverse events were assessed within 4 h of drug administration.</p> Results <p>Out of 540 screened TB patients, a total of 159 adult patients with schistosomiasis-TB coinfection were enrolled. Median age was 40&#xa0;years (Interquartile range (IQR): 35- 46). Out of 151 infected patients who were assessed at follow-up, 74 (49.0%, 95% confidence interval (CI): 40.4, 57.0) were cured (no eggs detected in stool samples at follow-up). The parasitological cure rate was lowest among those with moderate infection intensity 13.0% (three out of 23). The egg reduction rate (ERR) was found to be 76.4%. On multivariable regression analysis, high baseline infection intensity (adjusted prevalence ratio (aPR) = 1.93 95% CI 1.42–2.62; p &lt; 0.001) and being overweight (aPR = 1.77 95% CI 1.09–2.85; p = 0.02) were significant factors associated with cure rate at 3-week’ post-treatment. Of the 155 treated patients who received the drug, 48 (31.0%, 95% CI 23.9–38.1) were observed to present with at least one adverse event, with abdominal pain being the most common (29.7%, 46 out of 155). On multivariable analysis, high baseline infection intensity (aPR = 2.19 95% CI 1.34–3.56; p = 0.002) and changed stool consistency (soft stool aPR = 2.22 95% CI 1.22–4.03; p = 0.009, loose stool aPR = 2.29 95% CI 1.19–4.41; p = 0.01) were significant factors associated with occurrence of adverse events post-treatment.</p> Conclusions <p>This study observed very low parasitological cure and egg reduction rates following single dose of praziquantel treatment in the presence of Rifampicin-based anti-TB regimen. The observed low efficacy may be attributed to the drug-drug interaction. Since the study lacked drug plasma concentration data and comparison group, it only reflects the drug’s effect as observed. Future research with a pharmacokinetic study component and comparison group is needed to gain more evidence on the observed efficacy.</p>