Active listening in everyday settings is challenging and requires substantial mental effort, particularly in noisy settings. In some cases, effortful listening can lead to significant listening-related fatigue and negatively affect quality of life. However, our understanding of factors that affect the severity of fatigue is limited. Hearing aids and cochlear implants (CIs) can improve speech understanding and thus, potentially, reduce listening effort and fatigue. Some research supports this idea for adult hearing aid users with mild-to-moderate hearing loss, but similar work in CI users is very limited. This study examined (1) longitudinal changes in listening-related fatigue in new and established CI users, and (2) relationships between demographic and audiologic factors and preimplantation and postimplantation listening-related fatigue. Participants included an experimental group of 48 adult CI candidates receiving either a unilateral implant (n = 46) or simultaneous, bilateral implants (n = 2) and a control group of 96 experienced (>12 months experience) adult CI users (50 unilateral, 46 bilateral). Listening-related fatigue was evaluated using the 40-item version of the Vanderbilt Fatigue Scale for Adults. Experimental group ratings were obtained before implantation and again at 0.5-, 1-, 2-, 3-, 6-, and 12-month(s) postactivation. Control group participants completed the scale twice-upon study entry and approximately 3 months later. Additional measures, including a social isolation and disconnectedness questionnaire, hearing handicap inventory, and the Effort Assessment Scale, were also administered at multiple time points. The role of these measures and select demographic and audiologic factors on preimplant and postimplant fatigue ratings were examined. Adult CI candidates reported significantly more fatigue, greater self-perceived hearing handicap, greater listening effort, and more social isolation than experienced adult CI users. However, significant reductions in fatigue and effort were observed within 2 weeks postimplantation. By 3 months, there were no significant differences in fatigue, effort, hearing handicap, or social isolation between new CI recipients and experienced CI users. Secondary analyses revealed that age at onset of hearing loss (before or after 2 years of age) and subjective hearing handicap contributed significantly to the variance of preimplantation fatigue ratings (those with higher handicap reported higher fatigue). In contrast, variance in postimplantation fatigue ratings was not affected by age of hearing loss onset but was affected by gender (females reported more fatigue than males) and subjective ratings of effort, handicap, and isolation (those reporting more effort, handicap, and isolation reported more fatigue). Listening-related fatigue is a significant problem for many CI candidates, as well as for many experienced unilateral and bilateral CI users. Receipt of a CI significantly reduced listening-related fatigue (as well as listening effort, hearing handicap, and social isolation) as soon as 2 weeks post-CI activation. However, the magnitude of fatigue-related issues for both CI candidates and experienced CI users varies widely. Audiologic factors, such as hearing loss severity and aided speech recognition, were not predictive of individual differences in listening-related fatigue. In contrast, strong associations were observed between perceived hearing handicap and listening-related fatigue in all groups suggesting fatigue-related issues may be a component of perceived hearing handicap.