BACKGROUND: We conducted systematic reviews on the benefits and harms of screening compared with no screening or alternative screening approaches for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) in non-pregnant sexually active individuals, and on the relative importance patients' place on the relevant outcomes. Findings will inform recommendations by the Canadian Task Force on Preventive Health Care. METHODS: We searched five databases (to January 24, 2020), trial registries, conference proceedings, and reference lists for English and French literature published since 1996. Screening, study selection, and risk of bias assessments were independently undertaken by two reviewers, with consensus for final decisions. Data extraction was conducted by one reviewer and checked by another for accuracy and completeness. Meta-analysis was conducted where appropriate. We used the GRADE approach to rate the certainty of the evidence. The Task Force and content experts provided input on determining thresholds for important effect sizes and on interpretation of findings. RESULTS: Of 41 included studies, 17 and 11 reported on benefits and harms of screening, respectively, and 14 reported on patient preferences. Universal screening for CT in general populations 16 to 29 years of age, using population-based or opportunistic approaches achieving low screening rates, may make little-to-no difference for a female's risk of pelvic inflammatory disease (PID) (2 RCTs, n=141,362; 0.3 more in 1000 [7.6 fewer to 11 more]) or ectopic pregnancy (1 RCT, n=15,459; 0.20 more per 1000 [2.2 fewer to 3.9 more]). It may also not make a difference for CT transmission (3 RCTs, n=41,709; 3 fewer per 1000 [11.5 fewer to 6.9 more]). However, benefits may be achieved for reducing PID if screening rates are increased (2 trials, n=30,652; 5.7 fewer per 1000 [10.8 fewer to 1.1 more]), and for reducing CT and NG transmission when intensely screening high-prevalence female populations (2 trials, n=6127; 34.3 fewer per 1000 [4 to 58 fewer]; NNS 29 [17 to 250]). Evidence on infertility in females from CT screening and on transmission of NG in males and both sexes from screening for CT and NG is very uncertain. No evidence was found for cervicitis, chronic pelvic pain, or infertility in males from CT screening, or on any clinical outcomes from NG screening. Undergoing screening, or having a diagnosis of CT, may cause a small-to-moderate number of people to experience some degree of harm, mainly due to feelings of stigmatization and anxiety about future infertility risk. The number of individuals affected in the entire screening-eligible population is likely smaller. Screening may make little-to-no difference for general anxiety, self-esteem, or relationship break-up. Evidence on transmission from studies comparing home versus clinic screening is very uncertain. Four studies on patient preferences found that although utility values for the different consequences of CT and NG infections are probably quite similar, when considering the duration of the health state experiences, infertility and chronic pelvic pain are probably valued much more than PID, ectopic pregnancy, and cervicitis. How patients weigh the potential benefits versus harms of screening is very uncertain (1 survey, 10 qualitative studies); risks to reproductive health and transmission appear to be more important than the (often transient) psychosocial harms. DISCUSSION: Most of the evidence on screening for CT and/or NG offers low or very low certainty about the benefits and harms. Indirectness from use of comparison groups receiving some screening, incomplete outcome ascertainment, and use of outreach settings was a major contributor to uncertainty. Patient preferences indicate that the potential benefits from screening appear to outweigh the possible harms. Direct evidence about which screening strategies and intervals to use, which age to start and stop screening, and whether screening males in addition to females is necessary to prevent clinical outcomes is scarce, and further research in these areas would be informative. Apart from the evidence in this review, information on factors related to equity, acceptability, implementation, cost/resources, and feasibility will support recommendations made by the Task Force. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42018100733 .