Appearance of new skin and/or nerve lesions during or after fixed duration of multi drug therapy (MDT), both in multibacillary (MB) and paucibacillary (PB) leprosy, is not uncommon. It could be a lesion due to reaction (type 1 or type 2), relapse due to multiplication of persisting or drug resistant bacilli or reinfection due to re-entry of lepra bacilli from outside. It is relatively easier to recognize the lesions due to classical reaction, both clinically and histopathologically. However, the differentiation could be difficult in other situations, especially when many of the relapse cases may present with features of reaction at the onset. Similarly, sometimes in late reversal reaction in addition to development of classical acute inflammation of old lesions, many of the patients developed multiple fresh new lesions without any sign of inflammation. We report a study of group of 28 relapsed leprosy cases, who developed new skin and/or nerve lesions at greatly varying time intervals (3 months to 22 years) after stopping MDT. Of these 28 patients, 11 were MB (1 LL,6 BL and 4 BB) and 17 were PB (12 BT, 4 TT and 1 Neuritic) at their first treatment. They reported to the Urban Leprosy Center (ULC) of Dr R M L Hospital during the period of 5 years (2002-2007). All patients came through self referral, 13 of them (46.4%) had received MDT outside our hospital (regular in 11 cases and irregular in 2 cases, as per the patient's statement), while the rest 15 had received full MDT regularly from our center (irregular in 1 case). All previously 11 MB cases developed new skin lesions of MB type (1 LL to LL, 3 BL to LL, 3 BL to BL, 1 BB to BL and 3 BB to BB). Of the 17 cases PB at their first treatment, 16 developed new lesions of PB type. Out of 4 TT cases, 1 had new lesions of TT, 1 BT and 2 LRR type lesions. Of the 12 BT cases at first presentation, 9 had BT, 1 secondary neuritic and 1 presented as LRR, while 1 BT case had new lesions of BL type. The one pure neuritic leprosy case presented as neuritic case only, after an interval of over 20 years. The post-MDT intervals of appearance of new lesions were 3-6 months in 5 cases (Group A), 8-30 months in 13 cases (Group B), from 3-10 years in 4 cases (Group C) and 15-22 years in 6 cases (Group D). All patients were successfully treated with a second course of MDT, as per the spectrum of the disease according to the number of fresh lesions. The likely cause of new lesions in group A (<6 months interval) could be either (1) mild type 1 reaction or (2) early relapse due to inadequate MDT. Similarly, the new lesions appearing in group B (0.5-3 years) could also represent mild type 1 reaction following improvement of CMI or a true early relapse. The possible causes of early relapse may be because of original misclassification or inadequate chemotherapy/irregular treatment or insufficient duration of therapy. In group C (3-10 years), the cause would most probably be late relapse, the possible causes of late relapse is either due to drug resistance and M. leprae persisters. When the time interval goes beyond 10 years (Group D), as in 6 of our cases, the possibility of reinfection can not be excluded besides causes of late relapse, since this period is usually considered equivalent to the maximum incubation period of lepra bacilli. In lepromatous leprosy, where the specific CMI against M. leprae is highly compromised, there is always a possibility of reinfection as long as the source of infection persists in the community and in such cases immunotherapy would be highly beneficial for prevention of reinfection. The post MDT time interval, lepromin test or drug resistance study both in vitro and in vivo may provide some clue to the mechanism responsible. All doubtful cases of new lesions with clinical presentation of type 1 reaction were diagnosed as relapse, through the therapeutic trial with oral prednisolone for 4-6 weeks and other cases. All cases with new lesions were treated with a second course of MDT (MB or PB) as per classification of new lesions.