Background: The first night effect (FNE) is a polysomnography (PSG) habituation effect in the first of several consecutive in-laboratory PSGs (I-PSGs). The ENE is caused by the discomfort provoked by electrodes and cables and the exposure to an unfamiliar environment. A reverse ENE (RENT) with an improved sleep in the first night is characteristic of insomnia, presumably because the video PSG in the sleep laboratory leads to a decrease in the negatively toned cognitive activity. Therefore, two or more I-PSGs are required for an accurate diagnosis. Although the FNE is well documented in I-PSG, little is known about the FNE and the RFNE in home-based PSGs (H-PSGs). Methods: This is a retrospective analysis of a recently published cross-sectional study using H-PSG. Sixty-three consecutive patients suffering from multiple sclerosis (MS) were investigated by two consecutive H-PSGs without video. The differences between the first and second H-PSGs were analyzed. The patients were classified into four subgroups: no sleep disorder, insomnia, sleep-related breathing disorders (SRBDs), and periodic limb movement disorder or restless legs syndrome (PLMD/RLS). Results: MS patients suffering from insomnia showed no RFNE. MS patients with SKIM or PLMD/RLS showed no reduced sleep efficiency but significantly less slow wave sleep. Furthermore, SRBD patients showed significantly less non-rapid eye movement (N REM) sleep, and PLMD/RLS patients were significantly awake longer in the first night after sleep onset (increased wake-after-sleep-onset time) and showed a higher rapid eye movement (REM) latency. Conclusion: SRBD and PLMD/RLS patients showed a significant FNE. Two consecutive H-PSGs are required in these patients to obtain a precise hypnogram even in the ambulatory field. In MS patients suffering from insomnia, no RFNE was found, and in insomnia patients one H-PSG seems to be sufficient.