There is little in the literature comparing experiences of patients with disabling and uniformly terminal illness (e.g. amyotrophic lateral sclerosis) and illness characterized by episodic disability and prognostic uncertainty (e.g. multiple sclerosis). This study aimed to compare experiences of disability, quality of life (QoL) and psychological well-being in ALS and MS. One hundred patients with ALS and MS were interviewed at baseline and at six months. Variables measured included function, health related QoL, individualized QoL and psychological distress. Despite the divergent illness experiences of ALS and MS patients, groups did not differ on individualized QoL or mental well-being, and distress was in the normal range. Despite marked deterioration in ALS patients' health, there was no change in mental well-being and QoL. Psychological well-being appeared more important in maintaining QoL (individualized QoL and mental aspects of health related QoL) than physical factors. At the individual level, there was evidence of psychological adaptation to deteriorating function, which underlined the role of specific illness related challenges in determining perceived life quality and emotional well-being. In conclusion, the complex interplay between psychosocial and illness specific factors such as certainty with regard to prognosis has considerable implications for well-being and life quality. Recognizing such factors is essential when designing clinical interventions to promote adjustment and self-management among patients with neurological conditions.