Ocular surface squamous neoplasia (OSSN) can be localised to the conjunctiva or, less commonly, diffusely spread over the conjunctiva and cornea. Localised OSSN can be treated by surgical removal with adjuvant cryotherapy and chemotherapy with low rates of recurrence. Diffuse OSSN is more difficult to treat without morbidity due to necessary reconstruction of the ocular surface after excision. Primary topical chemotherapy provides an alternative that avoids the potential complications of wide excision. This retrospective case series studied eyes with diffuse OSSN that were treated with topical 5FU 1% or topical MMC 0.04% as a primary therapy. Diffuse OSSN was defined as a lesion extending over five or more limbal clock hours or having extensive central or paracentral corneal spread. Thirty-two eyes were managed as treatment naive diffuse OSSN. Twenty-nine cases received MMC 0.04%, including one case that was partially surgically debulked prior to therapy. Seven out of the 28 cases (25%) displayed recurrence or persistence of OSSN. 5FU 1% was used in three cases of treatment naive OSSN and recurrence or persistence of disease was observed in all cases. Thirteen cases had previously undergone a single unsuccessful treatment course for diffuse OSSN, administration of a second treatment course was successful in six (46%) of these patients. A strategy of switching treatment protocol from 5FU 1% to MMC 0.04% following treatment failure was attempted in seven patients, and tumour clearance was achieved in four. Conversely, retreatment with 5FU 1% following treatment failure with MMC 0.04% was attempted in five cases, and tumour clearance was successful in four. In four patients, following treatment with MMC 0.04% or 5FU 1%, tumour clearance was ultimately achieved with excision and cryotherapy of a localised area of recurrence. No serious long-term complications were noted with MMC 0.04%, one case treated with 5FU 1% experienced a focal stromal melt. The authors conclude that diffuse OSSN often requires multiple treatment efforts when compared with localised disease. Switching chemotherapeutic regimens following a treatment failure may be useful.