The 1980–81 IHF Women's Cup Winners' Cup was the fifth edition of IHF's competition for European women's handball national cup champions. It was contested by 16 teams, two more than the previous edition.^[1]

1965 European Cup runner-up Spartacus Budapest defeated Bane Sekulić Sombor in the final to win its first European trophy, following the steps of Ferencvárosi TC as the second Hungarian team to win the Cup Winners' Cup.

	Round of 16						Quarterfinals						Semifinals						Finals
	Sportist Kremikovtsi	31	23	54
	GS Romano	6	14	20
							Sportist Kremikovtsi	17	19	36
							SEW Hoorn	6	17	23
	WAT Fünfhaus	11	10	21
	SEW Hoorn	9	14	23
													Sportist Kremikovtsi	21	13	34
													Spartacus Budapest	27	16	43
	Vorwärts Frankfurt	12	8	20
	Rostselmash Rostov	8	11	19
							Vorwärts Frankfurt	15	12	27
							Spartacus Budapest	11	17	28
	Spartacus Budapest	20	11	31
	Štart Bratislava	15	13	28
																			Spartacus Budapest	18	22	40
																			B. Sekulić Sombor	17	17	34
	TuS Metzingen	10	11	21
	AIA Tranbjerg	14	16	30
							AIA Tranbjerg	10	12	22
							B. Sekulić Sombor	15	14	29
	B. Sekulić Sombor	24	24	48
	ATV Basel	11	11	22
													B. Sekulić Sombor	25	20	45
													Västerås Irsta	14	16	30
	Västerås Irsta	13	19	32
	Nordstrand IF	9	13	22
							Västerås Irsta	19	15	34
							PLM Conflans	13	17	30
	PLM Conflans	20	25	45
	Avanti Lebbeke	10	12	22