Current evidence on whether electronic cigarettes (ECs) pose respiratory risks is unclear, due to confounding by cigarette smoking; evidence among never-smoking individuals is needed. Following a narrative review and critical appraisal, a systematic review assessed possible respiratory outcomes prospectively associated with EC use among individuals who never smoked. Bias risk was evaluated using Joanna Briggs Institute tool. Ten eligible studies examined outcomes of self-reported respiratory diagnosis, symptoms, and lung function. Eight examined adults and three examined youth (with overlap). Overall, seven studies showed no significant association between respiratory outcomes and EC use among never-smoking individuals (P>.05). Evidence for coughing and wheezing symptoms varied by model specification. Overall, EC use by never-smoking individuals is not associated with risk of severe respiratory outcomes, but may be associated with mild coughing/wheezing. Further research is needed using larger samples, long-term follow-ups (>5 years), and information on detailed patterns of EC use.