In a progressive resistive strengthening programme, healthy individuals gain strength initially through neural adaptation followed by increases in muscle mass. Programmes are designed to maximise these responses. The physiological mechanisms of strength gain in RA are unknown, but their identification will help to develop more effective exercise programmes. The aim of this study was to investigate the responses to a 12-week isometric handgrip strengthening programme in female subjects with RA. Fourteen right-handed female subjects with RA and 14 age-matched female controls participated in a 12-week right handgrip strengthening programme. Maximum grip strength (MGS) and disease activity were measured serially over 12 weeks. Forearm muscle volume was measured using MRI at baseline and 12 weeks. Significant gains in right handgrip strength were noted in both groups, the gains being most marked in those with RA: mean (SD; range) MGS (mmHg) in RA group at baseline 105.1 (48.1; 34-108) and 174.8 (76.4; 50-340) at 12 weeks. Mean (SD; range) MGS in control group at baseline 311.7 (49.6; 220-370) and 357.0 (67.1; 250-540) at 12 weeks. Significant increases in forearm muscle volume occurred in the controls, correlating with gains in strength. No such changes were noted in the RA group, indicating that improvements were solely related to neural adaptation. Response to strength training in RA differs from those of healthy individuals. Significant gains in strength in individuals with RA can occur due to neural adaptation without gains in muscle mass during a strengthening programme. This has implications for the design of rehabilitation programmes for such subjects.