Individual differences in adjustment during a disease's course determine psychological response and outcome. This study aimed to investigate prospectively whether coping with health stressors and self-sacrificing defense style could predict psychological adjustment and health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA). Seventy-four consecutive RA patients attending a rheumatology clinic were assessed for psychological distress (SCL-90-R), sense of coherence (SOC scale), self-sacrificing defense style (Defense Style Questionnaire-88), disease activity (DAS-28), pain, disability (Health Assessment Questionnaire) and HRQoL (World Health Organization Quality of Life Instrument, Short Form) at baseline and 5 years later. Multiple regression and moderator analyses were carried out. The results showed that disease activity (p < .001), pain (p = .005), psychological distress (p = .031), social relations HRQoL (p = .042) and environment HRQoL (p = .020) significantly improved over time. SOC was found an independent predictor of improvement in psychological distress (p = .003), overall general health (p = .002) and social relations HRQoL (p = .004); self-sacrificing independently predicted environment HRQoL (p = .042). The self-sacrificing defense style moderated the relationships between improvement in pain and improvement in overall general health (p = .024) and between improvement in pain and improvement in social relations HRQoL (p = .006). These findings indicate that, in RA, SOC predicts improvement in psychological distress and HRQoL over time, while a self-sacrificing defense style moderates the relationship of pain with HRQoL in the long term. These variables may partly explain inter-individual differences in adaptation to RA. Therefore, the design of psychotherapeutic trials targeting the patients' defensive profiles and coping with health stressors capacities is an important research perspective.